Dundee Drug Discovery Unit Annual Report 2024

Drug Discovery Unit

Today’s Science: Tomorrow’s Medicine

Foreword

Because of my background in drug discovery for diseases of neglected patients I have been an advisor to Wellcome for many years in particular as an observer to the scientific advisory boards of the Drug Discovery Unit (DDU) and the Wellcome Centre for Anti-Infective Research (WCAIR) from their inception. Both initiatives have been established as desperately needed resources to make new medicines available to neglected populations as commercial pharmaceutical organisations insufficiently address these needs.

During these years the DDU, later very successfully associated with WCAIR, evolved into a globally outstanding integrated drug discovery and preclinical development operation. It is currently one of the very best in any academic environment. The focus areas are neglected infectious diseases such as Chagas disease or leishmaniasis caused by kinetoplastid parasites. The kinetoplastid portfolio also includes two compounds in clinical phases as a key indicator of productivity. There are several compounds in preclinical phases (see the kinetoplastid portfolio later in the report). Furthermore parasitic diseases such as malaria, cryptosporidiosis and schistosomiasis are addressed at the DDU. Here the pipeline includes one clinical compound and several at earlier stages. A third effort targets tuberculosis resulting in a preclinical compound and several earlier ones.

This impressive pipeline which is the key success criterion of a drug discovery and development initiative was realized because of the success of DDU/WCAIR to have attracted over the years about 130 outstanding scientists with multiple backgrounds and skills and to have built a network of partners amongst the leaders in the drug discovery and development ecosystem globally.

Essential for the success of DDU/WCAIR are not only the professionally run drug discovery and development projects but very importantly the leading edge platforms developed in Dundee that are contributing to all projects and are also available to academic scientists outside Dundee interested in finding new medicines for neglected populations. These globally recognized platforms include for example a target platform, constantly evolving medicinal chemistry methods including automation and a rather unique and outstanding group focusing on identifying and deconvoluting targets found in phenotypic screening and thus contributing both to basic knowledge and drug discovery. A platform addressing new animal and in vitro models has resulted in a completely new way to discover and develop medicines for Chagas disease. DDU/WCAIR is also developing an exciting AI-driven platform for this expansion and optimisation.

The mutual interaction of the projects and platforms as core functions is a key factor contributing to the success of DDU/ WCAIR and experience shows that this makes drug discovery and development very much more efficient than working in project-limited silos. It is therefore essential for the entire neglected diseases research community that this combined project-core functions platform model continues and be further developed.

As the focus of DDU/WCAIR is neglected patients, many in Africa and South East Asia , it is satisfying to see that DDU/ WCAIR is establishing several initiatives aiming at capacity building of scientists in endemic countries, such a symposia and workshops in the Ghana and Brazil hubs. In addition web based drug discovery and development related lectures make the DDU/WCAIR unique experience available to many scientists in low- and middle-income countries in Africa and throughout the world. A conference in Ghana in 2025 will bring many scientists from both the more developed countries as well those from endemic countries with less resources to learn from each other.

In conclusion the DDU and WCAIR have successfully established themselves as key academic contributors to medicines for neglected populations and should be an example to other such initiatives.

Professor emeritus Paul L. Herrling, PhD

Our vision

A world where everyone has access to safe and affordable medicines which allow individuals to manage their health, preventing diseases impacting their lives.

Our mission

To use our world-leading expertise, working in global partnerships, to develop new medicines for diseases of unmet medical need that affect millions of people across the world and have a global economic impact.

Our purpose

To deliver high quality drug candidates that will translate from the lab to the clinic. We do this through science-led development of the path to the clinic, application of drug discovery innovation and collaboration.

Introduction to the DDU

The Drug Discovery Unit (DDU) is unique: a complete drug discovery engine delivering candidate drugs, de-risked drug targets and commercialisation opportunities across multiple disease areas within a UK university.

What we do

The DDU tackles unmet medical need through small molecule drug discovery, bridging the gap between academic scientific research and commercial and charitable drug discovery and development. We draw on the best of these worlds, employing highly skilled, experienced scientists from academic and pharmaceutical industry backgrounds, with a professional, pioneering approach to our work.

We have two core areas of activity

→ Anti-infectives drug discovery

→ Innovative targets and pathways

Anti-Infectives Drug Discovery

In Low- and Middle-Income Countries (LMIC), more than 3 billion people are at risk from diseases such as malaria, TB, leishmaniasis, Chagas disease, cryptosporidiosis and schistosomiasis. As well as these diseases which predominantly affect LMIC countries, COVID is still a major issue in these countries.

Existing treatments can be expensive, difficult to administer, unsafe and/or increasingly ineffective as the pathogens that underlie these conditions develop resistance. Our overall goal is to generate lead compounds suitable for further development with our partners and, ultimately, to identify candidate molecules for entry into pre-clinical and clinical development.

Innovative targets and pathways

Disease experts and academic researchers continue to discover new biological processes which could be drug targets for major clinical indications. However, these targets are very often not sufficiently validated for licensing into pharmaceutical company portfolios or for spin-out company investment. The DDU is committed to bridging this gap by developing chemical assets that can advance our understanding of the underpinning biology and, ultimately, establish proof of concept in gold standard pre-clinical models of disease.

How we do it

We collaborate with partners globally to identify potential drug targets, lead compounds, candidate drugs and novel tools and approaches to develop improved treatments for a wide range of debilitating and deadly diseases. The DDU has the full repertoire of professional, industry-standard expertise and infrastructure required for early-stage drug discovery. These disciplines work together closely within an integrated management structure.

Medicinal and Synthetic Chemistry

Compound Management

Computational Drug Discovery

→ Design, synthesis and development of drug-like compounds from hit validation and expansion through to preclinical candidate, guided by computational approaches, bioassay and drug metabolism and pharmacokinetics.

→ New synthetic design and synthesis techniques

→ Automated high-throughput chemistry

→ Flow chemistry

→ Suite of Late-stage functionalisation reactions for optimisation lead optimisation

→ Full in-house Compound Management plating and storage facilities for latch racks and microplates.

→ High throughput liquid handling robotics utilising both tip based and acoustic technologies

→ Ability to perform Cherry Picking, Library Screening, Potency curve generation, and Plate Reformatting in 96, 384 and 1536 well plate formats.

→ Manage a high quality screening library comprising of over 350,000 compounds, comprised of Diversity screening sets and Focused libraries.

→ Manage and curate libraries for the DDU and external partners, supplying certain libraries globally.

→ AI and Machine Learning for virtual screening

→ AI and Machine Learning for compound design and optimisation

→ Data sciences to inform target selection

→ Design of fragment and compound libraries

→ Data management

Drug Metabolism and Pharmacokinetics

Hit Discovery

→ Industry standard in vitro and in vivo assays

→ Disease relevant in vivo models including 8HUM mouse (transgenic mice with human phase 1 metabolism)

→ Extensive use of imaging modalities with in vivo models.

→ Integrated PK/PD

→ Metabolite identification studies

→ Target-based and phenotypic screening technologies integrated with Mode of Action studies

→ Bespoke compound libraries

→ Multiple screening modalities for primary screening and secondary assays for both target-based and phenotypic assays. This includes technologies for both lead-like and fragment libraries. Technologies developed include -enzyme assays in multiple formats, high-content imaging, RapidFire Mass Spec, SPR, NMR, ITC and the X-CHEM platform

→ Structural biology platforms including X-ray protein crystallography, cryoEM, HDX.

→ Automated plate-based synthesis methodology direct into biology and DMPK assays

→ Disease relevant screening cascades

Accelerating Innovation

The DDU benefits from being part of the Wellcome Centre for Anti-Infectives Research (WCAIR). Wellcome funding has allowed investment to overcome the challenges the drug discovery pipeline faces. WCAIR innovation has focussed on improving 4 key areas critical to successful drug discovery:

→ Compound Design

Predicting the properties and activities of compounds before they are made, based on coherent data sets to train algorithms, and computational expertise and methods to derive them.

→ Chemistry Design and Synthesis

Improved and broader methods to rapidly and efficiently make optimally designed compounds at a scale to address key project goals.

→ Assay Design

Physiological and disease appropriate in vitro assays and animal disease models that are predictive of human clinical outcomes, where appropriate taking advantage of state of the art imaging.

→ Data Analysis

Use all available data to build better design models through machine learning.

By tackling these issues, we are impacting the whole drug discovery continuum to accelerate project progression (or closure) and thus increase the flow of candidate drugs. These improvements are available to others, through collaboration, knowledge exchange and training. Although WCAIR’s current focus is on leishmaniasis, Chagas disease, cryptosporidiosis and schistosomiasis, the ’toolbox’ of methods and approaches under development is applicable to other diseases.

Translational Funding

Strong partnerships with organisations funding scientific research for drug discovery has been fundamental to our success. We are grateful to Wellcome, the Gates Foundation, Medicines for Malaria Venture, the UKRI Medical Research Council, Global Health Innovative Technology (GHIT) Fund, and the Drugs for Neglected Diseases initiative, amongst others, for their continued support and encouragement. We align our research strategies and infrastructures with our funder’s aims and objectives and, together, deliver on our joint objectives to control or eliminate debilitating and fatal diseases.

Impact

Our impact is recognised not only by the progression of our compounds into pre-clinical and clinical trials with our partners but also by supporting partner academic groups to secure research grant funding to further explore disease biology using the tool molecules we produce.

Key numbers

4 compunds in clinical trials and 1 repurposed compound in antiinfectives

>£100m secured in research funding

130 experienced translational scientists

9 assets licensed to pharmaceutical companies

1 spin out company

The DDU in 2024

People

11 new people joined DDU

7 people moved from the DDU to new jobs

9 promotions

12 merit awards

1 Dundee Difference Award-collaboration

Communication and Public Engagement

17 papers published

9000

visitors to our Tackling TB exhibition

8 participated in 8 local Community Festivals and events

>100kg

donated >100kg of used PE equipment to Scrap Antics for recycling and community play sessions

1 poet in residence Giovanna MacKenna

Funding

£7.5m 11 new research grants started in 2024 worth £7.5 million in forward funding

£23.7m

9 new research awards confirmed to start in 2025 which will provide over £23.7 million in forward funding

Training

7 trainees Hosted from LMIC

30 months training in Dundee

74 people attended on-line Short courses

34 people attended face-to-face courses

14,000 views of WCAIR Training videos on youtube

Discovery

6341 internally synthesised compounds registered

531016 compounds screened in single point

18970 dose response curves in 79 assays

90 new assay SOPs registered

>650 binding assays by NMR

High throughput crystallography

→ >50000 crystal conditions screened

→ >720 crystal tested

→ 40 unique crystal structures solved using synchrotron light source

→ 5 new target structures

307 L

307 L E.coli culture and 87 L insect cell culture

Awards

Royal Society of Edinburgh

Mary Sommerville Award to the Drug Discovery Unit for team work and collaborative endeavour which has led to real world impact.

For their research work as the largest academic drug discovery team in the World. It demonstrates that multidisciplinary, tightly coordinated, and large-scale translational research with real-world impact is both possible and highly impactful. The team works extensively in neglected infectious disease, such as malaria, leishmaniasis, Chagas disease, and tuberculosis, and is a preferred partner for Wellcome and the Gates Foundation in achieving their missions in disease elimination. This impactful work appears in journals such as Nature, Science and PNAS, bringing international reputation to Scotland.

New DDU Principal Investigators

We are pleased to announce that through 2023 and 2024 three of the DDU Portfolio leaders were promoted to Principal Investigators in the School of Life Sciences, recognising their Scientific leadership and the impact of their research in their respective fields.

All three joined the DDU between 2006-2009 and so have been with the DDU since its inception. They have all grown their careers within the DDU progressing from research scientists , to team leaders and then Portfolio leaders. The recognition by the University of Dundee of their standing within the global research community is well deserved.

Dr Beatriz Baragaña

Beatriz is the apicomplexan portfolio leader in the Drug Discovery Unit (DDU). The Baragaña lab is focused on delivering effective and safe treatments for malaria, cryptosporidiosis and schistosomiasis exploiting novel biological pathways.

Beatriz graduated with a BSc in Chemistry from University of Oviedo (Spain) and a PhD in Organic Chemistry from the same university under the supervision of Prof. Barluenga. She went on to join Prof. A. P. Davies’ lab at Trinity College (Dublin) followed by an industrial postdoctoral position as Medicinal Chemist at Bayer AG (Wuppertal, Germany). She moved to Scotland in 2001 and joined Avecia (now Piramal Pharma) where she became a team leader working in antibody drug conjugates for the treatment of cancer. In 2007 she joined Prof. Ian H. Gilbert’s group at the University of Dundee.

Beatriz leads a portfolio of projects for malaria and schistosomiasis drug discovery and also led  the DDU cryptosporidiosis drug discovery programme. The projects in her portfolio are at various stages along the drug discovery pathway and involve an extended network of international collaborators both in industry and academia. Beatriz works closely with biologists, chemist, computational chemist, crystallographers, and pharmacologists to deliver leads and pre-clinical candidates with novel mode of actions for these infectious diseases. The most advanced compound discovered by her team, M5717 (DDD489) has recently demonstrated single dose cures of malaria infections in a Phase I clinical study. The DDU malaria team has been awarded the prestigious Medicines for Malaria Venture Project of the Year Award twice (2014 and 2018).

Read more, dundee.ac.uk/people/beatriz-baragana

Dr Laura Cleghorn

Laura is the Tuberculosis Portfolio Leader in the Dundee Drug Discovery Unit (DDU) where she leads a team of multi-disciplinary researchers focussed on identifying novel inhibitors with the potential to be progressed toward pre-clinical candidate selection and evaluated as a new therapy for TB.

Laura obtained a BSc(Hons) in Chemistry from the University of Edinburgh then worked at Organon Laboratories as a graduate medicinal chemist before moving to the University of Leeds where she obtained a PhD in Organic Chemistry in the lab of Prof. Ron Grigg. In 2006, Laura joined the newly formed Drug Discovery Unit as a medicinal chemist, initially working on Human African Trypanosomiasis, before moving to the Tuberculosis group in 2013, where she became the Portfolio Leader in 2020, and was afterwords promoted to the position of Reader in 2022.

The research in Laura’s group spans the drug discovery pipeline from identifying and progressing novel screening hits through to late-stage optimisation towards pre-clinical leads and ultimately new therapeutics. Multiple strategies are employed to achieve the goal of identifying molecules targeting new pathways or those exhibiting improved profiles against a known mechanism of action. This is a highly collaborative research program where the work is coordinated with an international network of collaborators to maximise impact.

Read more, dundee.ac.uk/people/laura-cleghorn

Dr Manu De Rycker

Manu is Head of Translational Parasitology and Portfolio Leader for the kinetoplastid and antifungal drug discovery programmes at the Drug Discovery Unit (DDU). Manu holds a Master of Science in bioscience engineering from the University of Ghent,

Belgium and a PhD in molecular genetics from the University of Cincinnati, Ohio, USA. Following postdoctoral work with Professor Peter Parker at the Cancer Research UK Lincoln’s Inn Field laboratories (London), he moved to the DDU at the University of Dundee in 2009 to develop high-content imaging assays for the newly started visceral leishmaniasis drug discovery programme.

Manu now heads the group that develop and run cell-based assays for the parasitology and antifungal programmes in the DDU. The team has successfully built extensive screening cascades for Leishmania donovani and Trypanosoma cruzi  that comprise high-throughput primary screening assays as well as advanced secondary assays with high physiological relevance, including assays for persister parasites. These cascades have proven pivotal to rapidly identify new compounds with the best chance of demonstrating in vivo  efficacy. For this work the team were co-recipients of the 2024 DNDi Project of the Year award. The group also investigate fundamental biology relevant to drug discovery, enable new modalities for anti-infective drug discovery and work on developing a screening cascade for Cryptococcus drug discovery.

As Portfolio Leader for Kinetoplastid Drug Discovery Manu leads a substantial drug discovery programme focused on delivering new pre-clinical candidates for Chagas disease.

In collaboration with GSK this programme has developed two new pre-clinical candidates for visceral leishmaniasis. Manu works closely with biologists, chemists and pharmacologists to deliver further candidates for these neglected tropical diseases. In 2024 the team were awarded the Biochemical Society Award for Industry and Academic Collaboration. Recently Manu has also started building an antifungal drug discovery programme, to tackle deadly invasive fungal diseases that disproportionately affect people in low- and middle-income countries.

Read more, dundee.ac.uk/people/manu-de-rycker

Public Engagement

In line with the University of Dundee’s core strategic mission focused on social purpose, public engagement has been an essential part of our work for many years.

As part of the Wellcome Centre for AntiInfectives Research, we benefit from a skilled and experienced public engagement team. This has allowed us to explore innovative ways of engaging with people. This includes science art collaborations, site-specific theatre, museum exhibitions, poetry, and more. We have hugely benefitted from our long-standing partnership with the community in Stosbwell.

This long-term, strategic approach to engagement has seen us become a valued part of our city’s cultural landscape. 2024 saw a great deal of activity in our public engagement programme. Over the course of the year, we:

→ Completed the run of our Tackling TB exhibition in Dundee’s historic Verdant Works museum, seeing over 9000 visitors

→ Took part in Dundee Science Festival, Dundee Women’s Festival, Dundee Pride, and Dundee’s Festival of the Future

→ Saw our Public Engagement lead recognised at the University’s inaugural Dundee Difference Awards with the Collaboration Award

→ Worked with students from both our Medical Art MSc course and undergraduates from Product Design

→ Joined in the School of Life Sciences’ Plant Power event at the University’s Botanical Gardens

→ Visited multiple community events in our partner neighbourhood of Stobswell through the year

→ Spoke and presented a poster at the Microbiology Society Conference, focused on how to co-develop exhibitions with cultural partners

→ Adapted our existing activities to support the University’s strategic priorities around student recruitment

→ Worked with senior pupils at Morgan Academy to develop a garden space at the school

→ Took our community partners to the national Engage conference, running a panel session

→ Ran PE training for colleagues across campus, as well as at with the James Hutton Institute, Heriot Watt University, and as part of European Researchers’ Night, to an audience spread from Ireland to Malta

→ Engaged with 3 community groups through our poet-in-residence, at Dundee international Women’s Centre, the Boomerang Reminiscence Group, and teens at the Arthurstone Art Group

→ Donated over 100kg of used engagement equipment to local charity Scrap Antics for community play sessions

→ Instigated a green regeneration project in the Stobswell West area

Spotlight on Augmented Discovery

Over the past year, we have seen a push to develop a platform for drug discovery, called Augmented Discovery. The essence of this is to combine Artificial Intelligence driven computational design with automated chemistry and bioassay as one integrated platform. We want to make this a “plug and play” system, with the most appropriate computational design, most appropriate chemistry strategy and most appropriate bioassay for the project involved.

The augmented discovery platform will better sample available chemical space and speed up the DMTA (Design-Make-TestAnalyse) cycle to rapidly identify developable scaffolds and series. The tight integration of AI, synthesis and testing will enable us to quickly identify the best performing AI algorithms for design.

We use Generative AI to design compounds, which uses wellestablished chemistry, that has a high chance of working and that we can use with our automated chemistry platforms. These platforms include plate-based and flow chemistry. The synthesised compounds are taken into the most appropriate bioassay. We have experimented with mass-spec based assays which do not necessarily require purification of compounds. This speeds up the DMTA cycle. However, the most appropriate bioassay for the project is used; this could for example be a phenotypic assay.

We have a large amount of well-curated biological, physicochemical and pharmacokinetic data which allows us to create deep learning models. These can be used to direct the generative design and help prioritise compounds for synthesis: multiparameter optimisation.

Based on data from an initial screen or hits, our start point is to design a plate of 96 compounds, focused around a provisional hypothesis. Some of the compounds are aligned closely to the original hypothesis (focused), and some are deliberately less close (diverse), in order to test the hypothesis. The data from the bioassay is then used to refine the hypothesis and subsequent chemistry. This is repeated until we can build a predictive mode, which allows a hit optimisation.

The cycle has been completed for several projects and we are now working to further validate it and roll it out.

Modernising the Design-Make-Test-Analyse cycle

Integrates computational drug discovery, automated chemistry and bioassay

Models

DMPK Models

Generative Design Activi Model

DESIGN MAKE ANALYSE TEST

Emergent Design Automated Synthesis

Plug & Play Rapid DMTA cycles

Xray CryoEM WACMS HDX SPR NMR ITC

Biochemical Screen

Spotlight on the Innovative Targets Portfolio

Although the focus of the DDU in 2006 was in neglected tropical disease, the founders, Professors Alan Fairlamb and Sir Mike Ferguson, always intended that the capabilities and expertise could be used to de-risk biology for globally important diseases such as Alzheimer’s and diabetes. The first steps on this road were taken in 2009 when a small group of scientists funded by an MRC grant started tackling innovative projects – the Innovative Targets Portfolio was born.

The team has grown to around 15 scientists and has developed a reputation across the UK and abroad for an open minded but pragmatic approach to new and untested biology. In essence, we seek collaborating scientists with biology that may be useful in treating disease from across academia and the industrial community. We then utilise the skills of the medicinal chemists, structural biologists, biochemists, cell biologists and computational drug discovery scientists to answer a series of deceptively simple questions.

Is the target biology able to be modulated in a meaningful way with small molecule inhibitors

→ If so, can we improve the properties of the tool molecules so that they can be used to interrogate the function of the target biology in a cellular context – ultimately to see if we can align the phenotype with a credible disease

→ If we can do this, we seek funding either from grants, industrial partners large or small or venture capitalists to further optimise the molecules to see if we can show a reasonable effect in animal models of disease

→ If the funding permits, we will take the molecules through to the point where they are pre-clinical candidates – poised for clinical trials

The foundation of the team’s efforts has been MRC Confidence in Concept and UKRI Impact Accelerator Awards. The funds and the efforts of the team have leveraged over £25 million in additional translational funds from industry and other sources. In addition, our collaborating scientist have received ~£15million for their research because of the wellcharacterised, novel chemical tools that have been provided to them as part of our collaborations.

The team has delivered data packages that have been involved in enabling the start-up of 6 companies and licenced 7 projects to industry.

2019

Research collaboration Alzheimer’s Parkinson’s License

Neuroinflammation

2020 License Dermatology

2021

2023

Co-development partnership Oncology

Research collaboration Parkinson’s

Our most advanced project is in phase 2 studies. This project was initially developed for Sleeping Sickness but was repurposed into oncology. The compounds were licenced to Pacylex in 2015. The clinical development they have undertaken showed unexpected efficacy in the phase 1 safety studies. As a result, the FDA decided to fast track the compound in 2022.

Our success in this area is a testament to the hard work and dedication of the Innovative Targets Portfolio scientists past and present. The Innovative targets portfolio and Drug Discovery Unit would like to thank all our academic collaborators without whom none of this would be possible. These include collaborators we have had in the UK universities (Cambridge, Dundee, QMUL, Oxford, Glasgow, Exeter, Bristol, Aberdeen) and abroad (Hannover, Barcelona, Alberta). We would also like to take this opportunity to thank our industrial partners (Bukwang, Takeda, Pfizer, GSK, AstraZeneca) and our major grant funders (UKRI, MRC, Gates Foundation, CR-UK, Tenovus & Scottish Enterprise).

Research collaboration Alzheimer’s Evaluation Oncology

2024 Evaluation and license agreement Oncology

Please get in touch if you have a novel target or biological hypothesis that could lead to new therapeutics, particularly those addressing CNS diseases or women’s health related indications

New Leadership for ITP

At the beginning of 2024 Prof. Mahmood Ahmed joined the School of Life Sciences to head up Medicinal Chemistry within the Drug Discovery Unit (DDU). Mahmood brings with him considerable experience in drug discovery from across Pharma, Biotech and Academia. Having started his industrial career with GSK (UK) in the early 2000s, he quickly took up the opportunity to head overseas and help establish a new integrated drug discovery centre in Singapore. He then transitioned to Academia, establishing a small drug discovery engine to support early-stage projects as well as advising the University TTO on life sciences commercialisation opportunities. Mahmood subsequently went on to co-found two biotechnology companies. Over his career to date, Mahmood has contributed to the identification and progression of multiple clinical stage assets.

Mahmood has more recently taken on the role of ITP lead, working closely with David Gray on the transition and is evolving a longerterm strategy focused on CNS-Women’s Health-Oncology; a key ambition is to enhance the number of Pharma Partnerships and progress projects towards advanced Lead Optimisation.

Portfolio Highlights

Kinetoplastid Portfolio

The kinetoplastid portfolio aims to develop much needed new medicines for Chagas disease. Chagas disease is a chronic disease that results from infection with Trypanosoma cruzi protozoan parasites. It affects millions of people in Latin America and beyond, and is a major cause of debilitating, and sometimes deadly, heart disease.

Portfolio overview

Our work in Chagas disease ranges from basic biology to precandidate selection. Main areas of activity are:

→ Study of persister parasites. Parasites that are less susceptible to drug treatment are a key challenge in Chagas disease drug discovery. A key goal is to develop higher throughput assays to assess the activity of new compounds against persisters.

→ New methodologies to improve the drug discovery path for Chagas disease: a major aim is to better understand the compound profiles required for Chagas drugs, this includes the in vitro profile, mode-of-action, and in vivo understanding of PK/PD drivers.

→ New modalities: we are exploring how to enable targeted protein degradation approaches for kinetoplastid diseases. We use a science-directed approach to achieve this, often through development and implementation of new methods and approaches.

→ The 4WAY001 series is our most advanced series, which shows clinical level efficacy in an animal model of chronic Chagas disease and we are working towards identifying a pre-clinical candidate in this series. This project is being conducted in collaboration with GSK, DNDi and the University of Washington. We have also identified multiple other series that act through the same promising mode-ofaction which provide backup for 4WAY001.

→ Our TCT02 series has entered lead optimisation and we have secured funding from MRC to deliver a preclinical candidate from this series.

Key Highlights from 2024

We accepted the 2024 Biochemical Society “Industry and Academic Collaboration Award” at the Biochemical Society Protein Dynamics & Transient Interactions meeting in September.

Funders and Collaborators

Visceral leishmaniasis - GSK899/DDU651

Visceral leishmaniasis – GSK245/DDU143

Chagas disease – 4WAY001

Chagas disease – 4WAYbackups

Chagas disease- multiple series

Chagas disease- phenotypic hits

“In the Kinetoplastid portfolio, we investigate parasitic diseases like Chagas disease and Leishmania where there are very few treatment options available. Working towards finding drugs for these neglected diseases is incredibly rewarding and exciting because we are continually discovering new information about these parasites and problem solving how we can use it to find a cure. As a chemist within the DDU, I enjoy the collaboration that exists between the multi-disciplinary teams. It is interesting to learn how our medicinal chemistry decisions impact the biology and DMPK of a compound in real life situations. The accessibility of the different teams cultivates effective discussions and lets us drive the research forward together.”

Joanne, Medicinal chemist

“Having recently joined the Kinetoplastid portfolio, which focuses on diseases such as Leishmaniasis and Chagas disease, I have been delighted to see how the collaborative and multidisciplinary environment in the DDU helps accelerate our research and drug discovery efforts. As a biologist, it has been really interesting for me to learn from the chemistry expertise within the group and see how the decisions made by the chemists in the drug discovery process impact the biology. Working in a field that could benefit human health is something I am hugely passionate about and I am excited to continue striving towards tackling these neglected diseases with the incredibly supportive DDU group.”

Abbie, Biologist

Key publications:

Short-course combination treatment for experimental chronic Chagas disease. Sci Transl Med. 2023 Dec 13;15(726):eadg8105. doi: 10.1126/scitranslmed.adg8105. Epub 2023 Dec 13. PMID: 38091410; PMCID: PMC7615676.

Authors: González S, Wall RJ, Thomas J, Braillard S, Brunori G, Camino Díaz I, Cantizani J, Carvalho S, Castañeda Casado P, Chatelain E, Cotillo I, Fiandor JM, Francisco AF, Grimsditch D, Keenan M, Kelly JM, Kessler A, Luise C, Lyon JJ, MacLean L, Marco M, Martin JJ, Martinez Martinez MS, Paterson C, Read KD, SantosVillarejo A, Zuccotto F, Wyllie S, Miles TJ, De Rycker M.

In this paper we show how a five-day course of a benznidazole –cytochrome b inhibitor combination can achieve full efficacy in an animal model of chronic Chagas disease. This work opens the possibility of reducing duration and adverse effects of current treatments for Chagas disease.

Validation of Trypanosoma cruzi inactivation techniques for laboratory use. PLoS One. 2024 Apr 18;19(4):e0300021. doi: 10.1371/journal.pone.0300021. PMID: 38635818; PMCID: PMC11025933.

Authors: MacLean LM, Ariyanayagam M, Sastry L, Paterson C, De Rycker M, Fairlamb AH.

In this paper we validate a range of methods to inactivate Trypanosoma cruzi parasites to allow safe downstream processing. This will be a valuable resource for other groups working with T. cruzi

Antifungals

Our programme to develop phenotypic screening assays for Crypcococcus neoformans and funded by the Tres Cantos Open Lab Foundation, made excellent progress and we now have multiple assays in place to assess compound activity against multiple C. neoformans morphotypes. C. neoformans causes cryptococcal meningitis, which has high rates of mortality in immunocompromised people in sub-Saharan Africa. The current treatments have significant drawbacks, and our long-term goal is to develop better drugs, developed specifically for Cryptococcus.

Key Highlights from 2024

→ Carried out a hit discovery campaign and identified a set of selective fungicidal compounds.

→ Developed assays for encapsulated and titan cells, as well as a sterile cure washout assay.

→ Started a Cryptococcus PhD project under the University of Dundee’s Africa Doctoral Fellowship scheme.

Funders and Collaborators

Apicomplexan Portfolio

Aims to develop new medicines for three parasitic infectious diseases that cause considerable health impact in low- and middle-income countries : malaria, cryptosporidiosis, and schistosomiasis.

There were approximately 247 million cases of malaria and 619,000 deaths worldwide in 2022. The reduction in malaria has stalled and resistance to the current standard of care is rising in southeast Asia and Africa. New treatments are urgently needed to overcome this threat. Cryptosporidium is one of five most important diarrhoeal pathogens in infants under 2 years of age. Cryptosporidiosis causes severe diarrhoea in very young or malnourished children and HIV patients, and frequently leads to death, or stunting and delayed cognitive development in survivors. There is currently no targeted effective treatment for cryptosporidiosis. An effective treatment for cryptosporidiosis could save lives of hundreds of thousands of infants and children and improve their development.

Schistosomiasis is a disease caused by parasitic nematodes. People are infected when exposed to infested water and school-aged children are especially vulnerable to infection. Chronic infections can lead to liver damage, kidney failure, infertility and bladder cancer. WHO estimates that at least 236 million people required preventive treatment for schistosomiasis in 2019. Praziquantel is the only drug approved for this disease and it is used both for treatment and mass drug administration campaigns. There is a pressing need for new and more effective medicines to treat schistosomiasis.

Portfolio overview

Our projects cover hit identification to preclinical candidate selection.

→ Our schistosomiasis project, a collaboration with Prof. Karl Hoffman (Aberystwyth University) and Prof. Andrea Brancale and Prof. Andrew Westwell (Cardiff University) is focused on refining the drug discovery pathway for schistosomiasis and has received funding from Wellcome.

→ As members of the Malaria Drug Accelerator (MalDA), we collaborate with leading academic and industry partners to identify and exploit novel mechanisms of actions for antimalarial treatments.

→ We lead the Structure Drug Discovery Coalition (SDDC). The SDDC aims to apply structure-based drug design to deliver inhibitors for novel validated targets with proof-ofconcept in vivo efficacy for malaria and TB with funding from the Gates Foundation. Our current SDDC partner is the Seattle Structural Genomics Centre for Infectious Diseases (SSGID).

→ Compounds series developed by the SDDc for malaria or TB are further optimized by the DDU malaria or TB teams towards candidate selection.

→ We have started a new project to indentify and optimise fragment hits for P. falciparum KRS in collaboration with Prof. Frank Von Delft (Oxford University), Prof. Tomo Nozaki (University of Tokyo) and Paul Willis (MMV) funded by GHIT.

Key highlights for 2024

→ Our paper “Cryptosporidium lysyl-tRNA synthetase inhibitors define the interplay between solubility and permeability required to achieve efficacy” was published in Science Translational Medicine.

→ We joined forces with Novartis to advance our malaria series in lead optimization towards a new antimalarial treatment. The DDU is supported by funding from MRCDPFS for this project.

Funders and Consortia

Malaria- Cabamiquine

Cryptosporidiosis - KRS

Malaria- Pf AcAS

Malaria- Pf IleRS

Schistosomiasis phenotypic series

Malaria- Pf KRS

“Since I joined the DDU in 2014, working in structure-based approaches to discover new medicines for malaria has been an incredibly rewarding and impactful experience. The beauty of this approach lies in the ability to provide detailed insights into the molecular mechanisms of action and resistance, enabling the design of compounds that specifically target Plasmodium enzymes and pathways. Collaborating across disciplines within the DDU —from computational chemists, structural biologist to biologists and DMPK scientists—and with external partners has fostered innovation and a dynamic work and learning environment which I love. The complexity of malaria as a disease, combined with the necessity for innovative solutions, requires a constant commitment to face and solve complex problems and a passion for science. The projects are undeniably demanding, however, the collaborative spirit within our team and the shared goal of eradicating malaria drives us forward. Working in the development of new therapies for malaria at the DDU definitely taught me also the value of resilience, teamwork, and dedication to a job that can have an impact on human health and potentially save millions of lives.”

Barbara, Project leader

“Working in the field of Malaria has given me a greater appreciation for the challenges faced when targeting infectious diseases, both globally and from a medicinal chemist’s point of view. The multidisciplinary nature of the DDU, and the close-knit teams that we work in, makes it much easier to interact with other fields of science and see how this helps us progress towards our goals. As an early career chemist this experience along with the wider training opportunities provided by the DDU has been invaluable and I look forward to continuing my development in such a positive environment.”

Connor, chemist

Coronavirus Portfolio

The Coronavirus portfolio is funded by the Gates Foundation and has collaborated for 4 years within the CARE (Corona Accelerated R&D in Europe) consortium. The portfolio originated in early 2020 as a response to the COVID-19 pandemic and is now positioned with a focus on pan-coronavirus drug discovery in order to prepare for future coronavirus pandemics.

SARS-CoV-2, the causative virus of COVID-19, is part of a larger family of coronaviruses, which is broadly divided into 4 branches or genera; alpha, beta, gamma and delta. To date, most observed cases of human coronavirus infections have emerged from alpha and beta coronaviruses (such as SARS-CoV-2), although there is evidence that a delta coronavirus has been detected in humans. Therefore, developing new medicines with as broad an activity as possible is desirable.

Portfolio overview

We have pursued several targets within the COVID portfolio, but our current focus is on the methyltransferase activity of Nsp14, a dual domain protein involved in RNA processing and RNA CAP formation. The active site of Nsp14 is highly conserved across several genera of coronaviruses, making it an attractive potential target for pan-coronavirus activity. In addition to development of our lead series, we have several backup series with different properties. The team have worked hard over the past year to push the lead and backup series further forward and we have progressed them through several key milestones.

We have been able to successfully establish a collaboration on one of our projects with the Biomedical Research Unit of Novartis, a great achievement for the programme and an exciting prospect to take the lead series forwards. In the New Year we look forward to further developing this collaboration. We are also excited to explore new opportunities in other important virus families, both within our current network of valued collaborators and through forging new ones.

Key highlights for 2024

→ Important collaboration established between Novartis and the DDU in the COVID portfolio: dundee.ac.uk/stories/drugdiscovery-unit-and-novartis-join-forces-discover-newdrugs-malaria-and-future-viral

→ New X-ray crystal structures with compounds solved, enabling further rational drug design.

→ Proof of concept in vivo experiments successfully completed within CARE

Funders and Collaborators

“Starting recently in the Coronavirus portfolio at the DDU has been an incredible learning experience. The support from my colleagues and the collaborative environment have made it easy to adapt quickly, allowing me to grow while contributing to vital work in coronavirus research”

Matthew, Medicinal chemist

“The Coronavirus portfolio carries out research in house and we have many other collaborations in both academia and industry. Although the science can be challenging, it is a great learning experience and is very fulfilling. The DDU has some of the latest technology and is constantly moving forward in the science field. I feel very fortunate to have amazing colleagues in the DDU who are willing to share their knowledge and expertise in various aspects of research, thus allowing us to thrive and move forward.”

Shamshad, Biologist

“As a medicinal chemist, working in the COVID portfolio has been a rewarding challenge, aiming to address important challenges. The dedication and collaborative ingenuity of our team has enabled us to design and optimise compounds, turning complex problems into innovative solutions. It’s a privilege to contribute to science that has the potential to make such a profound and immediate impact on public health worldwide.”

Craig, Medicinal chemist

Lead series

New screens

Lead PoC

Tuberculosis Portfolio

The Tuberculosis (TB) team seeks to discover new drug candidates for advancement into clinical trials. Tuberculosis continues to be a significant worldwide concern. An estimated 10.8 million people fell ill with the disease in 2023, and 1.25 million people died from the disease (WHO Annual Report 2024). A key ambition of our work is to discover compounds ideally with unique mechanisms of action that complement existing therapies and provide new possibilities for disease treatment.

Multi- and extensively- drug resistant strains of TB continue to increase, so there is an urgent need to discover new drugs targeting novel pathways to overcome resistance to the front-line therapies and increase the arsenal of regimens that could be deployed to combat the disease. As a member of the Tuberculosis Drug Accelerator (TBDA) and European regime accelerator for new TB treatments (ERA4TB) we collaborate with a wide range of academic and commercial partners worldwide to pursue our objectives.

Our work is a true team collaboration, bringing together scientists from various fields. In this section you can read some reflections on being part of DDU and Tuberculosis team.

Portfolio overview

Our efforts on TB range from hit discovery through to preclinical candidate selection. Our main areas of activity are:

→ Phenotypic screening of compound libraries against TB (more than one million compounds screed to date) through collaboration with NIAID.

→ Collaborating with TBDA partners to elucidate targets for phenotypic screening. A key success of this year has been identifying the target for two of our early hit-to-lead projects.

→ Advancing identified compounds to late-stage evaluation to support further progression.

→ Target based projects focussing on vulnerable, novel targets with the aim of circumventing pre-existing resistance.

Key Highlights from 2024

→ A key success of this year has been identifying the cellular target for two of our new hit-to-lead phenotypic projects.

→ Phenotypic screening campaign 30k GHCDLv2 compound library initiated.

→ Multiple series evaluated at hit assessment stage

→ Our late-stage LO series V46 series 1 has undergone further advanced efficacy and toxicity studies to support future progression towards the clinic.

→ Secured new $6 million 3-year funding from the Gates Foundation “Lead Optimisation Towards Untapped Selection phase candidates (LOTUS)” due to start spring 2024.

Funders and Collaborators

V46 series 1: Phenotypic series

V46 series 2: Phenotypic series

Pks13 series1

Pheno series 2024-1

Pheno series 2024-2

DEL1 Pks13 series

Pheno series 2024-3

“The TB team in Dundee encompasses multiple projects at various stage gates and includes a range of chemical series that demonstrate efficacy against TB.  Working within the TB team has provided the opportunity to work within global collaborations and has provided insight on how the wider TB community approaches drug discovery and evaluation.  Working within our collaborations we have been able to demonstrate impressive in vivo efficacy for one or our lead series and hope to demonstrate further exciting results in future studies!  Continuing to work in the TB space is of vital importance, especially considering the negative impact the Covid 19 pandemic had on access to essential TB services.”

Laura, DMPK Scientist

“Since joining the TB team at the DDU I’ve had the opportunity to work on exciting and cutting-edge science at all stages of the drug discovery timeline. I feel privileged to work in such an experienced and knowledgeable team. Bringing together biology, DMPK, molecular interactions and chemistry into an integrated team has helped to improve my overall knowledge of the drug discovery portfolio and makes for a cohesive workplace.”

Emma, Medicinal Chemist

Innovative Targets Portfolio

Most academic research into disease biology is insufficiently validated for direct incorporation into pharmaceutical company pipelines. Consequently, an enormous amount of scientific research in UK universities fails be translated into public health benefit. Our Innovative Targets Portfolio (ITP) seeks to address this gap by translating academic research and novel drug targets into licensable data packages suitable to attract follow-on investment.

ITP sources innovative biology from leading investigators across the UK and beyond and forms active research collaborations and translational plans to validate novel targets with small molecule drug discovery. Data packages including novel chemical assets showing proof of concept in cell or tissue models are partnered with the BioPharma industry for onward development.

Translation of research excellence into tangible public benefit is at the heart of the University strategy and is evidenced by the impact from the ITP. We continue to deliver a strong pipeline of commercialisation opportunities and sustainable partnerships with industry.

Given the nature of innovative target drug discovery, this group within the DDU is exposed to many different types of disease biology and collaborations with both academia and industry.

Portfolio overview

We continue our work with large pharma (Takeda) and acknowledge the key insights and world leading expertise that our academic collaborators from Dundee, Queen Mary University of London and Cambridge bring to our Innovative Targets Portfolio. We are actively driving our commercialisation endeavours with the aim to launch either a new company or licence assets to pharma with projects going through evaluations in 2024. The portfolio is pleased to welcome the non-hormonal contraceptive programme into the portfolio this year as our lead project in our Women’s Health focus. Moving forward Women’s Health and CNS diseases will be the primary strategic areas for ITP.

Key Highlights from 2024

→ Our Pro-senescence programme with QMUL entered into evaluation with ValiRx this year see press release dundee.ac.uk/stories/new-method-discovered-halt-activecancer-cells

→ At the latter end of 2023 we entered into a collaboration with Takeda to continue our discovery of novel dementia therapeutics dundee.ac.uk/stories/takeda-dundee-and-cambridgereunite-fight-against-dementia

→ Prof. Mahmood Ahmed took over from Prof. David Gray as lead for the portfolio. Prof. Gray remains a project lead within the portfolio.

Funders and Collaborators

Oncology - Zelenristat (Pacylex)

Alzheimer’s disease

Gut Motility

Oncology – target 1

Oncology – target 2

Metabolism

Non-Hormonal Contraceptive (NHC): MCP09Phenotypic series

NHC01 / NHC02 / NHC03 Phenotypic series

NHC Multiple Phenotypic hits

Non-Hormonal Contraceptive project

Our non-hormonal contraceptive research is focused on small molecules that work via disrupting the function of sperm cells. Our promising lead series is proving effective in vitro by reducing motility, which prevents the sperm cells progressing through the female reproductive tract and should also prevent fertilisation if any of the sperm cells were able to reach the fallopian tubes and encounter an egg. Our lead compounds show good in vitro efficacy and excellent DMPK properties. In addition to the work on our lead series, phenotypic screening is providing us with new chemical starting points, with the aim to identify chemical series targeting alternative sperms functions, to increase the chance of success. We have 3 such series undergoing hit expansion, utilising the DDU’s Augmented Discovery platform.

Women’s health has historically been an under-funded and under researched area. As a result, our understanding of key parameters are decades behind similar research in other organs. This makes the drug discovery process even harder, as we have a poor understanding of molecular characteristics which could either help or hinder a drugs access to the female reproductive tract (FRT), an essential parameter for any drug which has this area as a target. Over the past 18 months the non-hormonal contraceptive team have developed a new method for determining drug concentration in the tissue and fluid of the rodent FRT and have recently received a new grant from the Gates Foundation to study drug distribution of molecules to the FRT of rodents. This will not only benefit the DDU non-hormonal contraceptive project, but the women’s health field, as a whole.

Key Highlights from 2024

→ Designed out the off-target issues we had on the lead series, while maintaining good potency and DMPK properties

→ Shown that our compounds give good female reproductive tract exposure in rodents, which we hope will translate to exposure in the female reproductive tract of humans

→ New hits identified from high throughput screening and initial hit expansion in progress, utilising our Augmented Discovery platform

→ Secured funding from the Gates Foundation for a new target-based non-hormonal contraceptive program

→ Secured funding from the Gates Foundation for a 15-month project to study drug distribution to the rodent FRT

Business Development in the DDU

Business Development in the DDU covers our anti-infective and Innovative Targets portfolios. It focuses on creating and maintaining synergistic partnerships with industry, securing diverse funding and commercialisation of DDU assets for patient benefit.

In 2024 our business strategy has been to build more strategic partnerships with Industry both in the Global Health and more commercial spaces, identify DDU spin out opportunities for 2025 and onwards, diversify funding to ensure sustainable growth, and build a network of industry and business partners in new disease areas.

This year we welcomed new leadership of our Innovative Target portfolio leadership and with this came prioritisation of Therapeutic Areas, with an initial focus on CNS diseases. Our Innovative targets will focus on building research collaborations with pharma and shifting the paradigm as to how academia can more effectively and synergistically align with industry to achieve greater impact of fundamental research output.

Highlights

→ Two research collaborations with Novartis: In 2024 the DDU partnered two programmes with Novartis Biomedical Research division to discover new drugs for 1. malaria and 2. novel antivirals for future pandemics. This collaboration highlights the unit’s collaborative approach to tackling diseases of unmet medical need and commitment to global access.

→ Overarching agreement with ValiRx and Initiation of Evaluation project

We entered into a five-year agreement with ValiRx, during which time, the ValiRx, will have the opportunity to review research projects from the DDU in oncology and Women’s health. The first Evaluation Agreement under the framework focuses on DDU collaborative project with QMUL on Prosenescence an exciting area of research has potential to be effective in treating of multiple cancer types, and many other disease areas, including those associated with healthy aging.

Myself and our Scientific Liaison, Carine De Marcos Lousa have been out and about a lot this year at partnering events including Bio Europe in the Spring and Bio International in the summer. Our main aim at Bio international was to engage and build our network in the Women’s health space a growing interest for our Innovative Targets Portfolio building on our ongoing Non-hormonal Contraceptive projected in collaboration with the University’s School of Medicine and National Phenotypic Screening Centre. Our Women’s health interest will bridge the gap between our focus on diseases of low- and middle-income countries and our Innovative Targets Portfolio. This is a growing area especially for Venture Capital and we have been actively growing our network here. We hope to tell you much more about this in our 2025 report.

We have hosted numerous pharmaceutical companies and, biotech companies in the unit as part of our ongoing and developing strategy to build long term collaborations and partner early to maximise the potential for translation to the patient using our combined knowledge and resources.

We have also been exploring the potential of leveraging some of our anti-infectives into the animal health space when for example these cannot be taken forward in human health. In this regard we have numerous follow ups for 2025.

“2024 was my second full year as Business Development Manager for The University of Dundee’s Drug Discovery Unit (DDU). It has been a remarkable year, marked by significant advancements and collaborations in the field of drug discovery. I would like to take this opportunity to thank my colleagues both in the DDU and at our Research and Innovation Services IP & Commercialisation team and Research contracts team, for their continued dedication, support and positive attitude. I would also like to thank all our industrial collaborators and partners old and new”. Charlotte Green, Business Development Manager, DDU

Supporting drug discovery capability building in low- and middle-income countries

The DDU Training Academy has been running since 2017 (under WCAIR Training) and aims to support drug discovery researchers in low- and middle-income countries. Falling in line with the scientific aims of the DDU, most of this training has focussed on groups and institutions working in the anti-infectives drug discovery field. We have developed a number of training programmes, from bespoke placements in Dundee, short courses covering the whole drug discovery process, or specific parts of that process, and online content freely available for people to watch.

We have hosted 47 trainees in Dundee from 15 countries since 2018, delivering over 300 months of training in medicinal chemistry, drug metabolism and pharmacokinetics, mode of action, assay development, and compound/data management. Trainees should return to their institutions with new skills to implement in their own labs, supporting the capacity development in their own countries. We have also developed and run a suite of both online and face-to-face courses, delivering to over 300 participants, either online or in-country. Aware that we cannot provide places for everyone, we have also developed a suite of online content which is freely available to anyone working in drug discovery to use themselves or incorporate into their own teaching.

On the WCAIR website Training section you can read about the trainees who have come to Dundee, the Short courses we offer and access our on-line training videos. wcair.dundee.ac.uk/training

Trainees

2024 saw us host 7 trainees with our chemistry or DMPK trainers. In chemistry, we first had two PhD students from Brazil. Marina and Gabirel were both in receipt of CAPES Scholarships and spent 6 months each with us. They were joined by Fritz, from Ghana, as part of a Gates Foundation funded project and finally Fernando joined us from Brazil.

In DMPK, our team hosted 3 researchers from Brazil, who are introducing new DMPK assays into their institutions in Brazil. Simone and Renata joined us from Sao Paulo, and Mario joined us from FIOCRUZ.

Courses

We delivered a series of short courses, both online and in person. Our online courses prove to be very popular (with approximately 10-15 applicants for each place), and we filled all the programmes throughout the year.

We have also delivered two courses in person this year. The first, Drug Discovery Mission, ran with support from University of São Paulo in Brazil. This course hosted 10 scientists who worked through a series of workshops to identify the lead compound for a real-life chemical series. This course was free of charge to scientists in São Paulo state.

Our Practical Aspects of Drug Discovery course ran in CSIRCentral Drug Research Institute, Lucknow, India. This course took 24 scientists through the drug discovery process from developing a target product profile, to the regulatory approval process. This course was free of charge to scientists working in India and provided a number of travel bursaries to participants.

Highlights of 2024

7 trainees in Dundee

30 months of training in Dundee

74 participants in online courses

34 participants in face-to-face courses

14k views on YouTube

Online Learning

Our online learning continues to develop, and our Reaction Set Up series has proven to be incredibly popular. This year we have had over 2,000 views on our training resources on the website. The training section on our YouTube channel is very popular, with over 20,000 hits since launching.

Hub support

We were awarded an Academy of Medical Sciences Networking grant which allowed us to bring together scientists from throughout Brazil who are either provide DMPK services, or can use them (either now, or in the future). Researchers in Brazil have long discussed the issues with low availability of DMPK assays in Brazil, and their desire to develop these further. We brought together 50 scientists from 28 institutions, companies or funders in 12 states. People were very positive about our offer to support and we are now looking for funding.

In Ghana we continue to support the development of a drug discovery hub. We support the Gates Foundation Malaria Drug Discovery programme, where we have taken trainees and sent teams out to KNUST in Kumasi, Ghana to help with DMPK. One of our trainees this year is part of this programme.

We are part of a successful application to the EU, and are proud to be a partner in the RAFIKI award which brings together groups from 8 institutions, in 6 different countries across Europe and Africa.

We also secured some funds to support intra-university placements in Ghana. Our partners had told us that being able to move students to other institutions in Ghana with different equipment and facilities is essential, however, often difficult to do due to lack of funding. We were successful in gaining some funds from the Global Challenges Research Fund to support this work. This will allow up to 10 funded placements throughout Ghana in 2024/25.

We hosted 3 fellows from MSD under the Richard T Clarke Fellowship scheme. They supported us by developing a report on institutions working in drug discovery in a number of countries in South East Asia.

New Name

We will be changing the name of our training activities to the DDU Training Academy. All the scientists and teams within the DDU support the training activities and this name helps us reflect their crucial support. Here is a preview of our new logo

Closing remarks

We work towards the end of another busy year. Lots has been going on. A significant achievement has been the partnering of two projects with Novartis Global Health: an antimalarial project and a coronavirus project. The interactions are working really well. It was good to have a face-to-face meeting in September to help build the teams together. The whole DDU won an award this year from the Royal Society of Edinburgh: The Mary Somerville Medal for Teamwork and Collaborative Endeavour. This is a great recognition of our teamwork and collaboration both internally and externally. Congratulations to all. Beatriz Baragaña, Leah Torrie, Tom Eadsforth and Nicole Mutter recently went to collect the medal on behalf of the DDU and a certificate for everyone in the DDU!

Many congratulations to Laura Cleghorn, who has been promoted to a Principal Investigator. Laura is doing a fantastic job leading the TB Portfolio within the DDU and interacting with a large number of partners in both the Gates Foundation TB Drug Accelerator and the ERA4TB IMI consortium. The TB portfolio has a rich pipeline of projects from hit validation through to candidate selection. Laura has been selected as the Vice Chair for the next Gordon Conference on Tuberculosis. This means at the following conference, she will be the chair. This is great a testament to her reputation.

This year, we have welcomed Mahmood Ahmed as the new Head of Chemistry. Mahmood has moved from the warmer climes of Singapore to Dundee. In Singapore, he worked for GSK and then was involved in translation and entrepreneurship, working with both Universities in Singapore and being involved in the development of start-up companies. It is great to have his new perspective. Mahmood has taken over running our Innovative Targets Portfolio (ITP); this has transitioned from David Gray over the last few months. I would like to personally thank David for his enthusiasm and hard work with the ITP over many years.

The training team have done a massive amount of work over the last year, with face to face courses being run in Brazil (twice) and India. There continues to be interaction with Universities in Ghana, with several team members going to Ghana to help with training and a number of scientists from Ghana have spent time in Dundee. Next year, we are coorganising a conference with the University of Ghana entitled Drug Discovery Africa. This is an exciting opportunity. The scientists in Ghana have obtained additional funding from the Gates Foundation and LifeArc to continue to build their antimalarial drug discovery programme. Our DMPK has been supporting DMPK networks in Brazil and Africa; it is really important to see people start to consider DMPK in their work.

We continue to have great papers coming out. We had some unusual press on our cryptosporidiosis paper, which has just come out in Science Translational Medicine. As a disease that impacts cattle as well as humans it was picked up by the farming community, so we were in some of the farming publications. We have a list of publications at the end of the report – please have a look through.

I would like to thank our funders and collaborators across the world. It is great to work with some many people with a passion for drug discovery and to be part of a global team. I also thank all of the people who help us on Scientific Advisory Committees – it is great to get an external comment on our work. Most of all I would like to acknowledge a great team of scientists in the DDU. It is great to see their dedication and hard work and the tremendous progress that we are making on multiple fronts.

Thank you all.

Professor Ian Gilbert Head of the DDU

Governance and Structure

DDU leadership

The DDU Leadership Team brings extensive industry experience to the Unit and has secured over £100M in translational funding since it was established in 2006. We share a drive and determination to improve the translation of academic research by working on novel, often unprecedented, targets and applying industry-standard processes and decision making. This has helped to make the DDU a partner of choice for pharma, funders and academic partners alike.

In 2024 we reorganised the Leadership structure to more effectively translate strategy and decision making into operational and research success within the DDU.

The Leadership groups are

Executive

Chair

Ian Gilbert Head of the DDU

Mahmood Ahmed Head of Chemistry & Innovative Targets

Portfolio Leader

Beatriz Baragaña Apicomplexan Portfolio Leader

Mike Bodkin Head of Computational Drug Discovery

Manu De Rycker Head of Translational Parasitology & Kinetoplastid Portfolio Leader

Charlotte Green Business Development Manager

Internal advisory board

Chair

Mike Ferguson Interim Dean School of Life Sciences

David Gray Head of Biology

Lisanne Gibson Vice-Principal (Research)

External advisory board

Tim Wells ex-CSO MMV

Sharon Peacock Master of Churchill College Cambridge

Sarah Hardy Venture Capitalist

Sir Nicholas White University of Oxford

Business

Chair

Charlotte Green Business Development Manager

Mahmood Ahmed Head of Chemistry & Innovative Targets

Portfolio Leader

Ian Gilbert Head of the DDU

David McBeth Vice-Principal Enterprise and Economic Transformation Science

Chair

Kevin Read Head of DMPK

Mahmood Ahmed Head of Chemistry & Innovative Targets Portfolio Leader

Beatriz Baragaña Apicomplexan Portfolio Leader

Mike Bodkin Head of Computational Drug Discovery

Laura Cleghorn TB Portfolio Leader

Manu De Rycker Head of Translational Parasitology & Kinetoplastid Portfolio Leader

David Gray Head of Biology

Operational

Chair

Catharine Goddard Manger, WCAIR

Catharine Goddard who oversees a number of working groups and interactions with university professional services for Finance, HR, communications, processes, DDU culture and career development.

You can read about the DDU leadership team on the DDU website, drugdiscovery.dundee.ac.uk/about/people

Advisory Boards and Committees

We are very grateful to the people who devote time to working on our scientific advisory boards. They provide us invaluable advice and help.

Kinetoplastid Portfolio SAC

The kinetoplastid SAC function is to analyse and provide advice regarding drug targets, prioritisation and progression of projects, and development of lead series. It comprises independent advisers with expertise in the fields of drug discovery, medicinal chemistry, anti-microbial therapy and clinical trials in addition to representatives of Wellcome. This SAC meets twice annually.

→ Graeme Bilbe (Chair) Senior Advisor, formerly Chief Scientific Officer, Research and Development Director, DNDi

→ Jeremy Burrows VP, Head of Discovery, MMV

→ Laurent Fraisse Research and Development Director, DNDi

→ John Kelly

Professor of Molecular Biology, Department of Infection Biology, London School of Hygiene and Tropical Medicine

→ Paul Leeson Director, Paul Leeson Consulting Ltd

→ Karine Malagu Group Leader, Medicinal Chemistry, Charles River, U.K.

→ Maria Jesus Pinazo Head of Chagas disease, DNDi

TB Portfolio SAC

The Tuberculosis SAC meets annually and comprises expert advisers from the field including representatives from the Gates Foundation and TBDA. The purpose of the SAC is to advise and analyse the progression of hit and lead series.

→ Peter Warner

Senior Program Officer, Gates Foundation

→ Valerie Mizrahi Director, Institute of Infectious Disease and Molecular Medicine, UCT

→ Nader Fotouhi

Chief Scientific Officer, TB Alliance

→ Anna Upton

Senior Vice President, Head of Tuberculosis Research and Development, Evotec

→ Robert Bates Director, Head of TB Discovery, GSK

→ Robert Jacobs

Pharma Consultant

→ Steve Berthel

TBDA Medicinal Chemistry Lead and Program Manager

Apicomplexan Portfolio SACs

Our schistosomiasis project was supported by two external advisors:

→ Tim Wells

CSO, Medicines for Malaria Venture

→ Trevor Perrior

Scientific Consultant

The MRC DPFS funded project is a collaboration with David Fidock at Columbia University. We thank James Duffy (Director, MMV) and Prof. Simon Ward (Cardiff University, MMV ESAC member) for their previous service as external advisors on this project.

The SDDc SAC meets bi-annually and includes representation from MalDA, TBDA, MMV, TB Alliance and BMGF:

→ Prof. Elizabeth Winzeler

UC San Diego and MalDA Program Director

→ Prof. Jim Sacchettini

TAMU and TBDA member

→ Dr. James Duffy Director, MMV

→ Chris Cooper

Senior Director, TB Alliance

→ Gang Liu

Senior Program Officer, Gates Foundation

Innovative Targets Portfolio SAC

Our ITP SAB support the selection and progression of innovative target proposals and projects. It comprises a number of highly regarded internal and external drug discovery experts. The SAB meets twice a year, with applications needing a quicker response being reviewed electronically in the interim.

→ Mike Ferguson Regius Professor of Life Sciences, University of Dundee

→ Mike Ashford Professor of Neuroscience, University of Dundee

→ Heather Giles CEO, CSO and Director Vapogenix Inc.

→ Paul Leeson Director, Paul Leeson Consulting Ltd

We were very sad to hear that Neil Thompson passed away in 2024. Neil was a very valued member of the ITP SAC and we will miss his insight and guidance.

Wellcome Centre for Anti-Infectives Research SAC

WCAIR SAC includes expert advisers in the fields of drug metabolism and pharmacokinetics, medicinal chemistry, antiinfectives drug discovery, toxicology and clinical trials. This international group meets once per year in Dundee. The SAC has a consultative function, advising both the host institute (UoD) and funder (Wellcome).

→ Graeme Bilbe (Chair) Senior Advisor, DNDi

→ Mike Blackman Professor of Molecular Parasitology Francis Crick Institute

→ John Kelly Professor of Molecular Biology, Department of Infection Biology, London School of Hygiene and Tropical Medicine

→ Paul Leeson Director at Paul Leeson Consulting Ltd

→ Julian Rayner Professor of Cell Biology, Cambridge Institute for Medical Research and Dept. Clinical Biochemistry, University of Cambridge

→ Isabela Ribeiro Head, Dynamic Portfolio Unit, DNDi

Chemistry Advisory Board

We have also established a cross-DDU Chemistry Advisory Board to assist with our translational research by advising on chemistry methodologies and strategies. This group of experts provides more direct support to our chemistry teams and portfolio leaders across the DDU to identify optimal ways of delivering research objectives and assessing innovative methodologies and approaches.

→ Professor Varinder Aggarwal Professor in Synthetic Chemistry, University of Bristol

→ Professor Tim Cernak Assistant Professor of Medicinal Chemistry and Chemistry, University of Michigan

→ Dr David Lathbury Astute Chemical Development Consulting Ltd

→ Dr Paul Leeson Director at Paul Leeson Consulting Ltd

→ Professor Adam Nelson Professor of Chemical Biology, University of Leeds

→ Dr Steve Taylor Founding Director at Celbius Ltd

→ Dr Adrian Wright Director, Orka Scientific Ltd.

Publications 2024

Abdul Rehman, S. A., Cazzaniga, C., Di Nisio, E., Antico, O., Knebel, A., Johnson, C., Şahin, A. T., Ibrahim, P. E. G. F., Lamoliatte, F., Negri, R., Muqit, M. M. K., & De Cesare, V. (2024). Discovery and characterization of noncanonical E2conjugating enzymes. Science Advances, 10(13), eadh0123. doi.org/10.1126/sciadv.adh0123

Aguado, M. E., Carvalho, S., Valdés-Tresanco, M. E., Lin, D., Padilla-Mejia, N., Corpas-Lopez, V., Tesařová, M., Lukeš, J., Gray, D., González-Bacerio, J., Wyllie, S., & Field, M. C. (2024). Identification and Validation of Compounds Targeting Leishmania major Leucyl-Aminopeptidase M17. ACS Infectious Diseases, 10(6), 2002–2017. doi.org/10.1021/acsinfecdis.4c00009

Andrade Meirelles, M., Almeida, V. M., Sullivan, J. R., de Toledo, I., dos Reis, C. V., Cunha, M. R., Zigweid, R., Shim, A., Sankaran, B., Woodward, E. L., Seibold, S., Liu, L., Mian, M. R., Battaile, K. P., Riley, J., Duncan, C., Simeons, F. R. C., Ferguson, L., Joji, H., … Couñago, R. M. (2024). Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens. Journal of Medicinal Chemistry, 67(21), 19143–19164.

doi.org/10.1021/acs.jmedchem.4c01594

Caldwell, N., Peet, C., Miller, P., Colon, B. L., Taylor, M. G., Cocco, M., Dawson, A., Lukac, I., Teixeira, J. E., Robinson, L., Frame, L., Seizova, S., Damerow, S., Tamaki, F., Post, J., Riley, J., Mutter, N., Hanna, J. C., Ferguson, L., … Pawlowic, M. C. (2024). Cryptosporidium lysyl-tRNA synthetase inhibitors define the interplay between solubility and permeability required to achieve efficacy. Science Translational Medicine, 16(770), eadm8631.

doi.org/10.1126/scitranslmed.adm8631

de Almeida, T. F., Cunha-Junior, E. F., Wanderley, J. L. M., Pacheco, J. da S., Pinto-da-Silva, L. H., Andrade-Neto, V. V., & Chaves, S. P. (2024). Editorial: Strategies in the drug discovery and development for leishmaniasis: immunomodulators, natural products, synthetic compounds, and drug repositioning. Frontiers in Cellular and Infection Microbiology, 14 doi.org/10.3389/fcimb.2024.1384244

Gardner, S., Jin, Y., Fyfe, P. K., Voisin, T. B., Bellón, J. S., Pohler, E., Piehler, J., Moraga, I., & Bubeck, D. (2024).

Structural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency. Nature Communications, 15(1), 2071. doi.org/10.1038/s41467-024-46235-6

Gruber, F. S., Richardson, A., Johnston, Z. C., Myles, R., Norcross, N. R., Day, D. P., Georgiou, I., Sesma-Sanz, L., Wilson, C., Read, K. D., Martins da Silva, S., Barratt, C. L. R., Gilbert, I. H., & Swedlow, J. R. (2024). Sperm Toolbox—A selection of small molecules to study human spermatozoa. PLOS ONE, 19(2), e0297666. doi.org/10.1371/journal.pone.0297666

Ibrahim, P. E. G. F., Zuccotto, F., Zachariae, U., Gilbert, I., & Bodkin, M. (2024). Accurate prediction of dynamic protein–ligand binding using P-score ranking. Journal of Computational Chemistry, 45(20), 1762–1778. doi.org/, doi.org/10.1002/jcc.27370

Izquierdo, M., Lin, D., O’Neill, S., Webster, L. A., Paterson, C., Thomas, J., Aguado, M. E., Colina Araújo, E., Alpízar-Pedraza, D., Joji, H., MacLean, L., Hope, A., Gray, D. W., Zoltner, M., Field, M. C., González-Bacerio, J., & De Rycker, M. (2024). Identification of a potent and selective LAPTc inhibitor by RapidFire-Mass Spectrometry, with antichagasic activity. PLOS Neglected Tropical Diseases, 18(2), e0011956-. doi.org/10.1371/journal.pntd.0011956

Lang, S., Fletcher, D. A., Petit, A.-P., Luise, N., Fyfe, P., Zuccotto, F., Porter, D., Hope, A., Bellany, F., Kerr, C., Mackenzie, C. J., Wyatt, P. G., & Gray, D. W. (2024). Application of an NMR/ Crystallography Fragment Screening Platform for the Assessment and Rapid Discovery of New HIV-CA Binding Fragments. ChemMedChem, 19(13), e202400025. doi.org/, doi.org/10.1002/cmdc.202400025

Ma, J., Veeragoni, D., Ghosh, H., Mutter, N., Barbosa, G., Webster, L., Schobert, R., Sande, W. van de, Dandawate, P., & Biersack, B. (2024). Superior Anticancer and Antifungal Activities of New Sulfanyl-Substituted Niclosamide Derivatives. Biomedicines, 12(7). doi.org/10.3390/biomedicines12071621

MacLean, L. M., Ariyanayagam, M., Sastry, L., Paterson, C., De Rycker, M., & Fairlamb, A. H. (2024). Validation of Trypanosoma cruzi inactivation techniques for laboratory use. PLoS ONE, 19(4 April), e0300021-. doi.org/10.1371/journal.pone.0300021

MacLeod, A. K., Coquelin, K.-S., Huertas, L., Simeons, F. R. C., Riley, J., Casado, P., Guijarro, L., Casanueva, R., Frame, L., Pinto, E. G., Ferguson, L., Duncan, C., Mutter, N., Shishikura, Y., Henderson, C. J., Cebrian, D., Wolf, C. R., & Read, K. D. (2024). Acceleration of infectious disease drug discovery and development using a humanized model of drug metabolism. Proceedings of the National Academy of Sciences, 121(7), e2315069121. doi.org/10.1073/pnas.2315069121

Norman, C., Schwelm, H. M., Semenova, O., Reid, R., Marland, V., & Nic Daéid, N. (2024). Detection of the synthetic cathinone N,N-dimethylpentylone in seized samples from prisons. Forensic Science International, 361, 112145. https://doi.org/https://doi.org/10.1016/j.forsciint.2024.112145

Pinzi, L., Conze, C., Bisi, N., Torre, G. D., Soliman, A., Monteiro-Abreu, N., Trushina, N. I., Krusenbaum, A., Dolouei, M. K., Hellwig, A., Christodoulou, M. S., Passarella, D., Bakota, L., Rastelli, G., & Brandt, R. (2024). Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule interaction. Nature Communications, 15(1), 1679. doi.org/10.1038/s41467-024-45851-6

Timmerman, A., Deventer, M. H., Andrews, R., Reid, R., Marland, V., Edwards, D., Pudney, C. R., Nic Daéid, N., Stove, C. P., & Norman, C. (2024). Waxy- or Putty-Like Materials as a Novel Drug Preparation for Synthetic Cannabinoid Receptor Agonists: Detection in Prisons and In Vitro Cannabinoid Receptor Activity. Drug Testing and Analysis, n/a(n/a).

https://doi.org/https://doi.org/10.1002/dta.3817

Xie, S. C., Wang, Y., Morton, C. J., Metcalfe, R. D., Dogovski, C., Pasaje, C. F. A., Dunn, E., Luth, M. R., Kumpornsin, K., Istvan, E. S., Park, J. S., Fairhurst, K. J., Ketprasit, N., Yeo, T., Yildirim, O., Bhebhe, M. N., Klug, D. M., Rutledge, P. J., Godoy, L. C., … Tilley, L. (2024). Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase. Nature Communications, 15(1), 937. doi.org/10.1038/s41467-024-45224-z

Drug Discovery Unit

School of Life Sciences

University of Dundee

Dow Street

Dundee DD1 5EH

contactDDU@dundee.ac.uk drugdiscovery.dundee.ac.uk drug-discovery-unit-university-of-dundee