DDU Annual Report 2022

Drug Discovery Unit

Annual Report 2022

At the forefront of drug discovery and innovation.

Foreword

I arrived at the University of Dundee two years ago. One of the impressive things I have found has been seeing the translational activities across the University, whereby fundamental discoveries are developed into new technologies and products. This is happening in multiple areas across the University. One of the key examples of this is the Drug Discovery Unit (DDU). Work from the DDU has led to five compounds being moved into clinical trials. Last year, we were all excited with the first clinical results of the malaria compound developed in the DDU and subsequently being taken into trials by Merck KGaA. The compound was able to cure people who volunteered to be infected with malaria with a single dose of compound. We are excited to hear that the compound is now about to start field trials with patients in Africa and look forward to hearing the results of these as they emerge.

The DDU has developed numerous interactions across the University of Dundee and more widely across the University sector. Through these interactions, predominantly with groups working on novel areas of biology, the DDU has been instrumental in turning novel biological discoveries into drug discovery opportunities. Importantly, the DDU has a track record of commercialising these programmes to further drug discovery and development either through licencing or co-development partnerships, with success in recent years in areas such as oncology and neurodegeneration. The DDU and Wellcome Centre for Anti-infectives Research (WCAIR)

also work with numerous groups to develop and implement new technologies, such as computational chemistry, within the drug discovery process making a step change in drug discovery in neglected tropical diseases.

It is now nearly three years since the COVID-19 pandemic started; an experience that has highlighted the threat of infectious diseases. The DDU has a major focus on infectious diseases, especially those affecting Low- and Middle-Income Countries (LMICs). For the diseases that the DDU has been working on, there is an urgent need for new medicines, due to the development of resistance to current drugs and/ or current medicines being ineffective or non-existent. I think that this is an incredibly important area of work, and one that the University of Dundee fully supports. Not only does the DDU develop potential drug candidates for these diseases they also are at the forefront of drug discovery and innovation in this area and the training of development of scientists in LMICs.

One of the initiatives that I have championed as Vice Chancellor, is our African Initiative. I am very happy to see the DDU tackling diseases endemic in Africa such as malaria, tuberculosis, schistosomiasis, cryptosporidiosis and leishmaniasis. Furthermore, it is exciting to hear about the collaborations that the DDU have with African Universities. Of particular note is Ghana, where the DDU and the WCAIR, are working with scientists to establish a Drug Discovery Hub in Ghana. This venture involves joint research programmes,

networking to bring together scientists within Ghana and training, both in Ghana and online and with scientists coming to Dundee as part of a training programme. It is pleasing to see this work advancing and scientists from both the DDU and WCAIR being involved in this partnership.

The key to the DDUs success lies with the incredibly committed and talented scientists and academic related staff within the DDU. They have worked tirelessly through the many stresses of the COVID pandemic and continue to work hard with the goal of developing new medicines. It is very pleasing to see the high international reputation of our staff and the leadership that the DDU is playing in international consortia and collaborations.

I look forward to new developments within the DDU, as we see current projects progress and future projects initiated with the development of new partnerships continuing their success in collaborative drug discovery.

Professor Ian Gillespie Principal & Vice-Chancellor University of Dundee

Photograph by Creative Services

Introduction to the DDU

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

Our mission

To translate world-class biology research into novel medicines, for unmet medical need, efficiently and successfully through collaboration and innovation in drug discovery.

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 (LMICs), more than three 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 LMICs, 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 chemistry

→ Design, synthesis and development of drug-like compounds

→ Invested in new synthetic design and synthesis techniques

→ State-of-the-art equipment and methodology

Drug metabolism and pharmacokinetics

→ Integrated DMPK group

→ Supports hit and lead optimisation programmes

→ Industry standard in vitro and in vivo assays

→ High-value mass spectrometry equipment to analyse biological samples

Hit discovery

→ Comprehensive range of liquid handling and detector technologies; including nanolitre acoustic dispensing

→ Target-based and phenotypic screening technologies

→ Bespoke compound libraries

→ Multiple screening modlities and instruments

Bioinformatics

→ Management and analysis of biological data

→ Statistics, computational science, databases, algorithms

→ Building 3D models of protein structures

Structural biology and biophysical techniques

→ State-of-the-art protein crystallography infrastructure

→ BLI, SPR, NMR hit finding and validation techniques

Computational drug design

→ Druggability assessment of protein targets

→ Selection of compound libraries

→ Virtual screening

→ Analysis of screening hits

→ Compound design using protein structure

→ Optimisation of drug-like properties in design

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 four 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.

Key numbers

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 and cryptosporidiosis, 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 Bill & Melinda Gates Foundation, Medicines for Malaria Venture, the Medical Research Council of UKRI, Global Health Innovative Technology (GHIT) Fund, and the Drugs for Neglected Diseases initiative (DNDi), 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.

5 compounds in clinical development 130 experienced translational scientists

6 new companies enabled with DDU assets

9 assets licensed to pharmaceutical companies £100m secured in research funding

The DDU and WCAIR have a great team of people. They have coped exceptionally well with the challenges and constantly changing situation of the COVID pandemic and the new post-pandemic world. We need to acknowledge their huge contribution. This year has seen great progress scientifically within the DDU and WCAIR, in both our drug discovery and innovative projects, some of which is described later in the report; this has been reflected in some great papers coming out.

The year 2022 has seen a lot of change for the DDU and WCAIR. We have had some key people move on. Paul Wyatt, the former Head of the DDU and Director of WCAIR moved onto a new start-up Sitala Bio; Julie Brady, former Business Development Manager has moved to a role at LifeArc; Fabio Zuccotto, who was head of the computational chemistry team has moved to Vertex and Louise Burns former Finance Manager is now the Senior Business Finance Partner for the Department of Science and Engineering, University of Dundee. However, we now have a new Head of DDU, Ian Gilbert, who acted as interim until September and then was appointed as the permanent new Head. The DDU also has a new Business Development Manager, Charlotte Green, who started her new role in August transitioning from her scientific liaison role for the innovative targets group (there is an introduction to Charlotte on page 14). Recruitment of a new heads of Computational Chemistry and Chemistry is ongoing. We have wished 24 colleagues’ success in their new careers and have welcomed 26 new starts across the DDU teams. Late breaking news is the promotion of Manu De Rycker to a tenured Principal Investigator – congratulations to him.

This year has seen more of a normalisation of working practices, following the restrictions of the COVID pandemic. It is great to see more face-to-face meetings. However, following our experiences of the COVID pandemic, we have introduced elements of flexible working recognising that international research does not happen neatly between 9am5pm. This allows DDU members to choose where and when

to work most effectively and maintain a healthy work-life balance. This year has also seen the resumption of in-person conferences and meetings with collaborators. The first tentative meetings took place in the Spring. A group from the DDU and Mode of Action group headed to a Keystone Malaria Conference in Breckenridge, Colorado. Although it was -120C outside, it was very warm and friendly inside and hugely profitable to re-connect with collaborators after over two years of Teams meetings. In May, Dundee hosted the first face-toface meeting of the Malaria Drug Discovery Accelerator in over two years. This was held together with the first meeting of the Structure-guided Drug Discovery Coalition since the DDU have taken over leading this.

The five disease portfolios (Apicomplexan, Tuberculosis, COVID, Kinetoplastid and Innovative Targets) continue to make headway, with compound series progressing in each of the portfolios. There are advanced leads in Chagas disease, cryptosporidiosis and tuberculosis and significant progress on early-stage projects within malaria, tuberculosis, COVID, male contraceptives and innovative targets. Lots of innovation is occurring both within the portfolio teams and the discipline teams, including new tools which are impacting the drug discovery programmes. The applications of new mouse models with humanised metabolic systems has given rise to particular interest both locally and with our collaborators. These are discussed in more detail later in this report.

This year has seen a new drug discovery programme commence in schistosomiasis, in collaboration with the Universities of Aberystwyth and Cardiff. We have organised three international meetings, two online and one face-to-face in London, with parasitologists, drug discoverers, disease and public health experts, and clinicians from Africa, Europe, North and South America. The aim of these was to share experiences and learnings in the drug discovery process and to understand what is required for drug discovery for this very complex disease. We have also started two new proof of concept programmes, one in antibacterials along with Megan

Bergkessel in the Division of Molecular Microbiology and one in cryptococcal meningitis, headed by Manu De Rycker, both funded through the Tres Cantos Open Lab Foundation.

Training has continued to be a strong theme this year for staff within the DDU and externally. We have organised leadership training, as well as discipline training for staff within the DDU. There have also been a variety of online and face-to-face courses run in Uruguay, Ghana and South Africa as part of the WCAIR capability building programme.

It has been exciting to see progress in working with partners in Ghana to help establish a drug discovery hub there. Two of the Universities in Ghana have obtained funding from the Bill & Melinda Gates Foundation to undertake a malaria drug discovery project. We are collaborators on this grant, along with H3D in Cape Town. We have had numerous training sessions with scientists in Ghana. MSD has also supported this work through their Richard T Clark Fellowship for Global Health programme. Three MSD staff visited Ghana to understand from the research groups areas they wanted to upskill and then delivered suitable training. We have had increasing interactions with scientists in Brazil and we are starting to develop further interactions there particularly in drug metabolism and pharmacokinetics (DMPK).

This year we have also implemented the Schrodinger tool, Live Design, which is a great tool to enable collaboration within the teams in Dundee. This should facilitate an even more integrated approach to drug discovery and help us to move projects along more swiftly.

We are all excited to see what lies ahead in 2023. We have exciting drug discovery projects across all our portfolios and we hope to see at least one preclinical candidate emerging next year.

Key Papers in 2022

→ Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs.

Nature Communications

→ Compounds enhancing human sperm motility identified using a high-throughput phenotypic screening platform.

Human Reproduction

→ Chemogenomics identifies acetylcoenzyme A synthetase as a target for malaria treatment and prevention.

Cell Chemical Biology

→ Repositioning of a diaminothiazole series confirmed to target the cyclin-dependent kinase CRK12 for use in the treatment of African animal trypanosomiasis. Journal Medicinal Chemistry

→ Anti-trypanosomatid drug discovery: progress and challenges.

Nature Reviews Microbiology

Case study

Effective drug discovery in a global pandemic

Shortly after COVID-19 lockdowns began in Scotland, the University of Dundee’s Division of Signal Transcription Therapy began expressing key proteins from the virus.  In particular, the methyltransferase nsp14 from SARS-CoV-2 was identified as a potential anti-viral target. DDU scientists had been working on the mammalian version of this enzyme and were then able to apply their expertise to start the process of drug discovery with the goal of developing potential new medicines to treat COVID-19.  This enzyme is key to the formation of the viral mRNA cap, which is important for the stability of the mRNA and in translation to form proteins. The nsp14 primary assay was developed using the RapidFire 400 Mass Spectrometry system and screening of large chemical libraries was started within a month of first obtaining the protein - a very fast turnaround in drug discovery.  The assay was published (doi.org/10.1177/24725552211000652) and later our collaborators were able to solve X-ray crystal structures of nsp14 (doi.org/10.1016/j.str.2022.04.014) - giving insights into the molecular mechanisms of the virus and enabling a crystallographic platform.  The DDU COVID team are making progress on developing novel leads for this target. The COVID team is part of a consortium called CARE (Corona Accelerated R&D in Europe, imi-care.eu), bringing together many strands of expertise.  The lead series of nsp14 has progressed steadily since the pandemic and is currently in proof of concept animal experiments.

References

Pearson L-A, Green CJ, Lin D, et al. Development of a HighThroughput Screening Assay to Identify Inhibitors of the SARS-CoV-2 Guanine-N7-Methyltransferase Using RapidFire Mass Spectrometry. SLAS DISCOVERY: Advancing the Science of Drug Discovery, 2021, 26, 749-756.

Carna A, Plewka J, Kresik L. et al ‘Refolding of lid subdomain of SARS- CoV-nsp14 upon nsp 10 interaction releases exonuclease activity. Structure, 2022, 30, 1050-1054.E2.

This work was funded by:

Image by Centre for Disease Control

Meet the team

An interdisciplinary team with a collective 168 years experience – who are as diverse in their hobbies as they are in their expertise!

Colin is a Medicinal Chemistry Team Leader focussing on the development of small molecules to aid current and future pandemics. Outside of work he loves to enjoy the outdoors, walking, running or cycling. As we go to press, Colin is moving onto a role in the TB portfolio.

De is particularly interested in applications of mass spectrometry in drug discovery. His free time is spent with family, playing badminton and watching sports.

Duncan, the COVID Portfolio leader, is a medicinal chemist who recently joined the DDU, with interests in all aspects of drug discovery. He enjoys the beach, playing the piano, and is Dad to a cheeky toddler.

Irene is a medicinal chemist interested in designing and synthesizing small molecules for pharmaceutical purposes. Beyond drug discovery, she enjoys long walks by the seaside and reading crime novels.

John is an experienced assay scientist, who has worked on many projects within the DDU. He is running target-based assays for this project. He is also a PhD researcher and photographer exploring themes of identity, representation, and queer visual culture at the Belfast School of Art.

Sandra is a biologist, performing biochemical assays, assay crash investigations, and helps build collaborations. She likes being organised, sunny days in winter, a good crime thriller and making four-item lists.

Lesley-Anne is a biochemist with 16 years lab experience. When she is not moving tiny amounts of liquid and being excited by pretty graphs, she spends her time playing the piano, video games, and being bad at Japanese.

Sean is a medicinal chemist with an interest in small molecule inhibitors, chemical probes and novel therapeutic modalities. He is a big fan of the outdoors and can usually be found bagging Munros at the weekend.

Shamshad is a committed bench biochemist with many years of assay development experience. Always happy to take on new aspects of project work, Shamshad is a good team player and networker. Away from work, Shamshad loves nature walks, family time and reading.

Suzanne is the DMPK representative for the team - this is more fun than it sounds as she gets to crush chemists’ souls by telling them their molecules are not good enough. When she’s not making chemists cry, she enjoys baking and cosying up with a good film and a glass of wine.

Xiao is leading the computational chemistry aspects of this project, with a special passion in computer aided drug design. She also enjoys reading books, binge-watching documentaries and playing video games.

Back row L to R: John Post, Sandra O’Neill, Sean O’Byrne, Xiao Hu, Irene Georgiou, Colin Robinson Front Row L to R: Lesley-Anne Pearson, Duncan Scott, Shamshad Afzal Ahmad

De Lin

Spotlight on Business Development

Charlotte Green, PhD, Business Development Manager for the DDU

Since August 2022 Charlotte has been operating as the Drug Discovery Unit’s Business Development Manager, a role in which she brings not only a broad scientific knowledge base but also a proven track record of successful drug discovery project management and leadership skills. Before commencing her new position within the Unit, Charlotte was employed as Scientific Liaison for our Innovative Targets portfolio, a challenging and fast paced role crucial for establishing and managing partnerships with both academic and commercial industry-based collaborators. With this experience Charlotte has become an invaluable member of the leadership team for identifying dynamic commercial opportunities which complement and challenge the expertise within the DDU.

Charlotte’s career began in academia with a ten-year fellowship focused career in metabolic disease during which she began her Novo Nordisk Fellowship, giving her an insight into industry led scientific research. With this combined experience Charlotte looked to fuse her love of academiabased research with a role that she could utilise her growing commercial and project management skills. With this goal in mind, she took up the challenge of Scientific Liaison within the DDU in 2018. Her role spanned the breadth of the drug discovery process; from triaging novel targets, assessment of commercial markets, building connections with both external academics and pharmaceutical companies, whilst also forging good working relationships with colleagues within the DDU and the wider scientific community at the University of Dundee itself.

Photograph by Creative Services

In her new role, Charlotte is focused on developing a DDU wide business strategy that ensures longevity for the DDU through maintaining and forging new synergistic partnerships, highlighting what sets the DDU apart from others.

“Although our portfolios are diverse, I believe our strength as a Drug Discovery Engine lies in our expertise, staff and focus to find new therapeutics.”

During the pandemic the DDU were successful in maintaining partnerships and workflows and were able to build a new and successful Coronavirus portfolio, an achievement made possible by utilising the already established and robust platforms within the DDU. With these workflows already in place within the Unit, new assets were quickly de-risked and moved forward smoothly into full programmes of research.

“The work we have been able to move forward in the COVID space highlights how quickly we can utilise our existing platforms to de-risk targets and move them forward efficiently across our different portfolios and areas of research. This is something I want to exploit more of, opening more opportunities for collaboration, with both internal and external partnerships, across the DDU.”

Charlotte’s new position allows her to remain an integral part of the ITP management team as well as being able to apply her insights of commercial and academic drug discovery experience to the wider DDU management team.

“I feel the DDU is moving into a new and exciting phase, with our new Head of the DDU, Ian Gilbert, bringing forward fresh ideas, alongside our Innovative Targets portfolio eager to connect with new opportunities and partnerships to not only build upon our existing knowledge but lead the DDU in innovative scientific partnerships. It is a very exciting time to be leading our business strategy.”

To find out more or discuss potential collaborations or business opportunities please contact Charlotte at c.j.z.green@dundee.ac.uk

Photograph by Creative Services

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 pre-candidate 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. We aim to better understand their biology, to find markers of the persister state and find new targets for these forms.

→ 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. 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.

Key highlights for 2022

→ New award from Wellcome to continue Chagas disease drug discovery

→ Advanced leads developed for 4WAY001 series and multiple series identified with same promising mode of action

“I knew from an early age that neglected diseases were something that I wished to pursue. I remember being curious about people with infectious diseases and used to think why were they not treated past a certain point? I discovered some of the diseases did not have treatments. Once at University then it became clear that to be working within Drug Discovery for Neglected Diseases would be a route worthy of my time and effort and be in line with my passion.”

Erika, DMPK

“Chagas disease is a truly neglected disease and drug discovery is extremely challenging. The progress we are making is very exciting, and I hope that one day we can deliver new treatments to a population that really needs them.”

Michael, Chemistry lead

“I like working in DDU because it combines stateof-the-art facilities and an international working environment in one of the top liveable places in Scotland. I also enjoy working surrounded by excellent researchers who are always willing to collaborate with each other.”

Marta, Parasitologist

“The highlight of the year for me is the that the parasitology team were able to pull together and generate a lot of data for key projects despite the difficult set of circumstances in 2022. The main reasons I like working at the DDU are that I get to work with parasites, which I continue to find fascinating, and be part of a multi-disciplinary team with the common goal of finding new treatments for NTD. I also really like working with people from all over the world.”

Lorna, Team Leader Parasitology

Visceral leishmaniasis - GSK899/DDU651

Visceral leishmaniasis – GSK245/DDU143

Chagas disease – 4WAY001

Chagas disease – 4WAYbackups

Chagas disease- multiple series

Funders and Consortia

Apicomplexan portfolio

Our teams work to develop new treatments for malaria and cryptosporidiosis, two infectious diseases caused by apicomplexan parasites. These diseases disproportionally affect children in Low- and Middle-Income countries, particularly in Africa. There is no effective treatment for the diarrheal disease cause by Cryptosporidium in malnourished infants. Resistance to current malaria treatments is spreading in Africa and Asia and this increases the need for new antimalarial medicines.

In addition, in our portfolio, we have a drug discovery project to discovery new treatments for schistosomiasis, an infectious diseases cause by worms that affects 250 million people per year.

Portfolio overview

Our projects expand from hit identification to pre-clinical candidate selection. We lead the Structure-guided Drug Discovery Coalition (SDDC). The SDDC aims to apply structurebased drug design to deliver Early Lead series for malaria and TB. We have a project in lead optimisation for malaria in collaboration with Eisai and MMV and a more advanced project at the late lead profiling stage for cryptosporidiosis in collaboration with Prof. Chris Huston (University of Vermont) and Eisai. Our schistosomiasis project is a collaboration with Prof. Karl Hoffman (Aberystwyth University) and Prof. Andrea Brancale (Cardiff University) and it is funded by Wellcome.

Key highlights for 2022

→ Our cryptosporidiosis lead has progressed to rat toxicological studies.

→ In collaboration with MalDA partners we published the validation Plasmodium acetyl-CoA synthetase as a promising malaria target: doi.org/10.1016/j. chembiol.2021.07.010

→ We have obtained proof of concept of efficacy for our acetylCoA synthetase inhibitors in a mouse model of malaria.

→ In May we welcomed our MalDA partners to Dundee for the first face to face meeting for the consortium since December 2019.

→ In September we organised a workshop in London to discuss drug discovery for schistosomiasis. More than 50 academic and industry experts discussed key challenges and proposed solutions to accelerate the discovery of new medicines.

“The highlight for me is getting to proof of concept of efficacy for PfAcCS, which represents a major goal for the development of compounds for this target. Being part of the apicomplexan team within the DDU also means being part of a wider international team focused on the same goals, with access to a wealth of knowledge, experience and support.”

Andy, Senior Biologist

“For me the highlight of the year was the MalDA/ SDDC meetings held in Dundee. I enjoyed finally being able to attend a work event in person and meeting many of the great people involved in the consortia.”

Joel, Structural Biologist.

Malaria- Cabamiquine

Cryptosporidiosis - KRS

Malaria- Pf KRS

Malaria- Pf AcCS

Malaria- Pf KRS BU

Multiple target-based series

Funders and consortia

“My highlight of the year was expanding the Schistosomiasis team and traveling down to London together for our Target Product Profile meeting. I think the Apicomplexan team works really well together, everyone is friendly and supportive”. Nicola, Medicinal Chemist Team Leader.

“It has been very exciting to work on a new antimalarial target and getting high quality hits from our screening campaigns. Being part of the Apicomplexan portfolio is a great pleasure; it is a challenging but friendly environment. The highly collaborative nature of our work and involvement of several partners across the world make the job rewarding and stimulating whilst contributing to the ambitious and relevant goal of malaria eradication.”

Luma, Biologist

Coronavirus Portfolio

The SARS-CoV-2 (COVID-19) pandemic is familiar to all of us and has had a huge impact on society. To date over 600 million cases have been recorded and 6.6 million deaths are officially attributed to COVID-19 globally. The concerted vaccination effort worldwide has been speedy and impressive and has enabled society to largely reopen. It is important to remember though that vaccinations are not 100% effective and certain groups of people cannot be vaccinated, leaving them potentially vulnerable. Currently three drugs are available for the treatment of SARS-CoV-2 infections; Remdesivir, Molnupiravir and Paxlovid. The former two are existing drugs which target RNA viruses, re-purposed for the treatment of COVID-19. Paxlovid itself owes its origins to a related small molecule inhibitor designed to target the 2002-2004 SARS outbreak. This highlights a further important point, the value of ‘pandemic preparedness’ –having molecules ready to go for if (when) the next pandemic emerges. Therefore SARS-CoV-2 drugs developed now may not only find utility in hospitalisation cases of COVID-19 now, but also in future outbreaks.

Key highlights for 2022

→ Three different modes of inhibition identified against nsp14

→ 34 crystal structures of nsp14 inhibitors obtained across three different series.

→ Sub-100 nM activity in cell-based anti-viral assays

→ First molecule shows evidence of activity in proof of concept mouse study

→ Nsp3 programme is continuing in collaboration with IKTOS within the CARE consortium

The coronavirus portfolio currently has two programmes within the IMI CARE consortium, nsp3 and nsp14. Nsp3 is an important viral protease that the virus uses to cleave the large viral polypeptide, releasing the necessary proteins needed for viral replication. Nsp14 is a key methyltranferase required in methylating viral RNA, such that the virus can evade the recognition mechanisms in human cells that would otherwise trigger an immune response to the foreign RNA. The nsp14 programme has achieved excellent steps ahead with potency both in the primary assay and the anti-viral cellular assay. This has been performed with our collaborators across Europe, bringing together disciplines such as medicinal chemistry, structural biology, enzymology, biophysics, virology and DMPK. The nsp14 is currently progressing a tool molecule into proof of concept experiments.

“Being part of WCAIR, my highlight of the year is developing mass spectrometry (MS) based high throughput screening (HTS) platform especially affinity selection MS (ASMS) in the unit. The ASMS enables rapid screening of large library of compounds (up to 50k compounds in one day) to identify ligands for specific target and will significantly accelerate the process of hit identification for projects across portfolios in the DDU.”

De, RapidFire expert

“Working on the CARE COVID project has been challenging in terms of the scientific questions we are striving to answer. However the individuals involved in the DDU COVID team and our CARE colleagues have been very supportive of each other throughout the project which has been rewarding to see and has helped the project to move forward.”

Sandra, Biologist

“The highlight of my year was progressing compounds into an animal model of COVID which is a major milestone for the project. Sharing this moment of success with the team was rewarding and satisfying. The impact of COVID has been immense and working with our team and collaborators to develop therapies for the virus is something I am excited and proud to be a part of.”

Sean, Chemist

“When I was 12 I wanted to be a ‘clinical biochemist’. I didn’t really know what it meant but I was clear that I wanted to do biochemistry that helped people. The ability to pursue my joy whilst also knowing that our research can have real world impacts is a great privilege of my life. I was so grateful to be able to come into the lab during the pandemic and feel like I was able to make a difference, and I am so lucky to have such an amazing group of colleagues to work with.”

Lesley-Anne, Biochemist

Tuberculosis Portfolio

The tuberculosis (TB) team aims to identify new drug candidates for progression towards clinical studies. We are focussed on identifying compounds acting on novel modes of action to complement the therapies that already exist and which offer new potential in the treatment of the disease. Multi – and extensively – drug resistant strains of TB continue to increase, so there is an urgent need to discover new drugs to overcome resistance to the front-line therapies. By targeting novel modes of action, the aim is that pre-existing clinical resistance will be reduced or non-existent. Prior to the COVID-19 pandemic, TB was the global leading cause of death due to an infectious agent. Some 10 million people are infected each year, and an estimated 1.5 million people died from TB in 2020. The extent to which the COVID-19 pandemic will have impacted TB diagnosis and treatment is yet to be established. Reduced access to healthcare during the pandemic, resulting in less TB cases being recorded is likely to set back years of progress on combatting TB. As a member of the Tuberculosis Drug Accelerator (TBDA) and European regime accelerator for new TB treatments (ERA4TB) we work with numerous academic and commercial partners across the globe towards achieving our goals.

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 screened to date) through collaboration with National Institute of Allergy and Infectious Diseases (NIAID) in the USA (Prof Clifton Barry).

→ Working with partners to identify the targets of phenotypic screening.

→ Target based projects focussing on high value, novel targets.

Key highlights for 2022

→ New award from the Bill & Melinda Gates Foundation, Designed optimised leads for infectious diseases (DOLFIN), kicked-off in March 2022

→ Our work on LysS as a novel target for TB drug discovery was published doi.org/10.1038/s41467-022-33736-5

→ New hit-to-lead series displayed proof of concept in vivo efficacy

→ Completed phenotypic screening of a large 140,000 compound library in partnership with the NIH

→ Screening completed and potent hits identified for a novel TB target

“I like working in the DDU because it’s important to me that I am working on something which could literally be a lifesaver for a lot of people. I feel like our research will make a difference in people’s lives.”

Alice, Structural Biologist

“It is really rewarding to contribute towards the identification of new drugs to tackle TB. This neglected disease is a major global cause of both mortality and financial burden. But due to its ‘low profile’ within the developed world, limited efforts are focused on it from ‘mainstream’ drug discovery efforts.”

Simon, Senior Biologist

“Working in the DDU has always been enjoyable and one of the best aspects, for me, is the cross disciplinary teamwork.”

Susan, Medicinal Chemist

DDU209-LysS

TBMMV46: Phenotypic series

ENA06: Phenotypic series

ENA03: Phenotypic series

Early Phenotypic series

LysS backup

Funders and consortia

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 biotech companies (Bukwang, Beactica), pharma (Takeda, GSK) and acknowledge the key insights and world leading expertise that our academic collaborators from Dundee, Oxford, Cambridge and Queen Mary University of London bring to our Innovative Targets Portfolio.

Key highlights for 2022

→ 2022 was an exciting year with one of our licenced projects entering phase 1 clinical trials for the treatment of non-Hodgkins lymphoma and advanced solid tumours via Pacylex (www.pacylex.com).

The first patient treated with PCLX-001 (formerly DDD86481) was reported in March 2022 (doi: 10.3390/ curroncol29030158 ) with trials continuing. In January 2023 PCLX-001 was granted Fast Track Designation for the treatment of adult patients with relapsed or refractory acute myeloid leukaemia (AML) based on the results from non-clinical studies and the ongoing nonHodgkins lymphoma trials.

→ ITP were back on the road at BioEurope Autumn partnering event (Leipzig) for the first time since the pandemic started in 2020. It was a great feeling to be networking in person and building new relationships face to face.

“For me a highlight of 2022 was the cross disciplinary training sessions. ITP work on a lot of different projects spanning multiple diseases, pathways and drug discovery techniques so understanding of different disciplines makes for a much better and more efficient project team.” Dinesh,

Biologist

Oncology- PCLX-001 (Pacylex)

Tauopathies

RNACapRx

Parkinson’s disease

Oncology

Ageing

Funders and consortia

“The development and application of our Interference library has been a step-change in our screening approach in ITP.”

Mary, Medicinal Chemist

Spotlight on our Synthetic Methodologies team

Chemistry is fundamental to the drug discovery process. Through funding from WCAIR, we have been looking at ways in which we can increase the efficiencies of our chemistry processes. This has taken a number of different aspects.

Plate-Based Chemistry

To speed up chemistry synthesis and screening we have invested heavily in the development and introduction of automated plate-based synthesis methodology. This approach can be carried out in 96- or 384-well-plates, allowing large numbers of analogues to be prepared.

It makes extensive use of computational chemistry in the design process, to generate many virtual compounds which can be filtered and selected by desired properties and then synthesis can begin. We make extensive use of robotics to automate the processes as much as possible. Another advantage is that it can be carried out on a very small scale, typically of the order of 0.1mg per compound which is two hundred times less than traditional methods used within the DDU.

The process is illustrated in the figure below and follows a design, make, test cycle using multiple rather than single samples per cycle.

We have optimised a variety of chemical reactions to be used with this platform. Where necessary we have also integrated specialised equipment when a conversion has a particular requirement; for example for rigorously inert conditions or for photoredox applications. We have also developed analytical and preparative LCMS methods combined with a calibrated evaporative light scattering detector to measure the quantity of purified compound avoiding the requirement to weigh very small amounts of material. We have established that in many cases the compounds synthesised in this way do not require purification before a biological assay, which further speeds up the process. This technology has been rolled out into multiple projects and series, allowing rapid establishment of structureactivity relationships. Since the development of the process over 7500 compounds have been synthesised and tested speeding drug discovery efforts.

Late Stage Functionalisation

We have been identifying and validating a dedicated set of reactions which allow functionalisation of elaborated molecules without extensive synthesis. This is useful to allow fast optimisation of late-stage molecules reducing the timelines to optimise compounds of interest.

Biotransformations

We are investigating the use of biotransformations of molecules using enzymes. Some of this work is being carried out in collaboration with a small company called Hypha Discovery Ltd. We are investigating which approaches give us access to molecules which are not easily made by conventional organic chemistry.

Flow Chemistry

We have developed a fully capable flow chemistry set up that has allowed the synthesis and use of unstable intermediates and the safe generation and use of carbon monoxide. The system has also been upgraded and used for electrochemistry and light driven chemistry increasing access to chemical space using these reagents and techniques.

In conclusion

The combination of developed and validated chemical technologies has allowed chemistry to be delivered to project teams that would otherwise have been difficult or impossible. The approaches developed have increased the range of molecules available to synthetic chemists and allowed faster delivery of compounds to speed drug discovery efforts.

This work is funded by Wellcome through the Wellcome Centre for Anti-Infectives Research.

Governance and structure

DDU leadership

The DDU Executive 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.

The DDU Executive are joined at monthly meetings by additional leaders from within the DDU selected from our portfolio and discipline leaders to form the DDU Leadership team. These extra voices provide important viewpoints and experience from across the DDU and work closely with the DDU Executive at a strategic level.

Head of DDU

Ian Gilbert

DDU Executive

Head of Biology & ITG Portfolio Lead

David Gray

Head of Chemistry

Head of DMPK

TBA

Extended Leadership Team

Laura Cleghorn

TB Portfolio Lead

Kevin Read

Head of Computational Chemistry

TBA

Head of Translational Parasitology & Kinetoplastoid Portfolio Lead Manu de Rycker

Apicomplexan Portfolio Lead

Beatriz Baragaña

Head of Business Development

Charlotte Green

WCAIR Manager

Duncan Scott COVID Portfolio Lead

Gary Tarver

Vincent Postis

Head of Synthetic Methodologies

Head of Molecular Interactions

Susan Wyllie

Head of Mode of Action

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

Susan Wyllie leads the highly successful Mode of Action group (modeofactiondundee.org). She has recently joined the leadership team, owing to the extensive and growing interactions with the DDU.

Catharine Goddard

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, Vice President, Head of Discovery, MMV

→ Laurent Fraisse, Research and Development Director, DND

→ 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, UK

→ Maria Jesus Pinazo, Head of Chagas disease, DND

TB Portfolio SAC

The Tuberculosis SAC meets annually and comprises expert advisers from the field including representatives from the Bill & Melinda 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, Bill & Melinda Gates Foundation

→ Valerie Mizrahi, Director, Institute of Infectious Disease and Molecular Medicine, University of Cape Town

→ 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

→ Paul Smith, Pharma Consultant

→ Steve Berthel, TBDA Medicinal Chemistry Lead and Program Manager

The GHIT and MMV funded projects are supported by

→ Paul Willis, Interim Head of Discovery, MMV

→ Dennis Smith, Consultant, MMV ESAC

→ Roger Bonnert, Consultant, MMV

→ Susan Boyd, Consultant, MMV and review by MMV ESAC annually

The SDDC SAC meets bi-annually and includes representation from MalDA, TBDA, MMV, TB Alliance and Bill & Melinda Gates Foundation:

→ Prof. Elizabeth Winzeler, University of California San Diego and MalDA, Program Director

→ Prof. Jim Sacchettini, Texas A&M University and TBDA member

→ Dr. James Duffy, Director, MMV

→ Chris Cooper, Senior Director, TB Alliance

→ Gang Liu, Senior Program Officer, Bill & Melinda 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

→ Robin Carr, CEO MYRICX Pharma

→ Heather Giles, CEO, CSO and Director Vapogenix Inc.

→ Neil Thompson, CSO Healx

→ Paul Leeson, Director, Paul Leeson Consulting Ltd

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, formerly Chief Scientific Officer, Research and Development Director 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, Paul Leeson Consulting Ltd

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

→ Steve Rees, Vice-President Discovery Biology at AstraZeneca

→ 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

UoD Advisory Group

The University has established an advisory group consisting of senior representation from the University Executive Group and School of Life Sciences Leadership Group. Meeting tri-annually to maintain connectivity between the DDU and University at a strategy level.

→ Prof Julian Blow, Dean of the School of Life Sciences

→ Prof Claire Halpin, Associate Dean Research of the School of Life Sciences

→ Mr Peter Fotheringham, Director of Finance

→ Dr David McBeth, Director of Research and Innovation Services

→ Anne Muir, Deputy Director of Research and Innovation Services

→ Mr Owen Adams, School Manager, School of Life Sciences

Finance

The DDU receives funding and support from charities, research councils, industry, private foundations and the University of Dundee. These monies are largely project specific and are managed in line with university charitable financial regulations.

The monies awarded to the DDU are inherently variable year-on-year due to the cycles of our research funding. Many awards are for 3 – 5 year programmes of activity, such as the Wellcome Centre for Anti-Infectives Research and Kinetoplastid Portfolio Award both of which were first recognised in 2017 and renewed in 2022.

2022 was a successful year for the DDU with 14 new awards. As well as the renewed Wellcome Funding, the DDU also received renewed funding for the TB portfolio from Bill & Melinda Gates foundation and the UKRI MRC Impact accelerator account to the innovative targets portfolio.

Annual income by the DDU demonstrates a managed growth over the period 2017 – 2022. This reflects an increased headcount from 70 to 130 directly funded scientists over the period as well as an increased cost of goods.

The DDU continues to be successful in attracting funding from a number of sources. Wellcome and the Bill & Melinda Gates Foundation are currently our most significant funders, reflecting the infectious diseases research within the DDU.

Drug Discovery Unit funder types

The DDU Leadership Team extend especial thanks to Ms Lisa Robertson our Finance Partner who manages the DDU portfolio of awards and other income.

Closing remarks

This year has been one of great change for me, taking over as interim Head of the DDU when Paul Wyatt left in March and at the beginning of October, taking over permanently. I feel very excited by this challenge and grateful for the support of my colleagues across the whole DDU and more widely from WCAIR and the Division of Biological Chemistry and Drug Discovery and the University as a whole. We are fortunate to have a great team working in the DDU. They are achieving some really exciting and innovative science critical to carrying out drug discovery. We also have a great set of collaborators in academia, industry, product development partnerships and with funding agencies. We have a large and valued involvement in big international consortia, such as the malaria and tuberculosis drug accelerators run by the Bill & Melinda Gates Foundation, HIT-NTD through Wellcome, as well as the IMI CARE consortium for COVID drug development and the IMI ERA4TB consortium for TB drug development.

The DDU is making great progress across a range of neglected infectious diseases, including Chagas disease, cryptosporidiosis, malaria, TB and COVID and have recently started a project in schistosomiasis. The DDU has and is continuing to build a lot of experience in this area and drug discovery for infectious diseases will continue to a large

proportion of activity. Unfortunately, there is no shortage of infectious diseases which require new medicines. The Innovative Targets group continues to make exciting progress across a number of projects. The recent change in funding from the MRC Confidence in Concepts to the MRC UKRI Impact Accelerator Account will allow the Innovative Targets group to take a longer-term view and to focus into their work in particular areas and spin out more companies.

Being based in the University of Dundee gives the DDU many opportunities; to develop new methods, explore disease biology and develop new drug discovery projects. Through our base within the University we have seen some paradigm shifting technologies and approaches developed and implemented in our research, such as the Mode of Action group, mice with humanised metabolic systems and our understanding of persister biology. It is exciting to see collaborations developing within the University, for example with the Centre for Targeted Protein Degradation, the MRC Protein Phosphorylation Unit, the Division of Molecular Microbiology and the School of Medicine. I believe that there are other important collaborations that we can develop in order to bridge the gap and de-risk academic drug discovery for industry and to drive projects towards the clinic.

It is important to continue to innovate in our approaches for drug discovery, this has been a key impact of WCAIR. In collaboration with others we have delivered new work-flows in areas such as: developing physiologically relevant assays and animal models of disease; computational methods for compound optimisation; high throughput chemistry; imaging techniques; and biophysical methods for screening and assay.

I am really pleased by the training programmes that we have been implementing in synthetic and medicinal chemistry, drug metabolism and pharmacokinetic and also in leadership and management skills. We have great staff and we need to help them and support them to develop as scientists and managers. We are also very fortunate to be supported by a great team of administrators, laboratory managers and technicians, contracts managers and finance officers.

I particularly thank our collaborators and partners, in Dundee and across the world, for the great interactions that we have, which is critical for our work. Drug discovery is hugely complex and it is important to work with others in these endeavours. I also would like to thank our funding agencies, without whom none of our work would be possible.

Professor Ian Gilbert Head of the DDU

Notes

Photography unless otherwise credited by John Post. Thank you

Drug Discovery Unit

School of Life Sciences

University of Dundee

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Dundee DD1 5EH

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