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.

→ 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