VIRTACs - Protein Degradation as an Anti-Viral Strategy

Lead Research Organisation: University of Glasgow
Department Name: School of Chemistry

Abstract

As highlighted by the current Covid-19 pandemic, viruses are a constant threat to human health and prosperity. Viral infections kill millions of people every year and population growth, international travel and climate change mean that human populations are increasingly vulnerable to emerging viral threats. Further to the severe morbidity and mortality caused by viruses, lost productivity and livestock deaths mean viruses place a considerable burden on the global economy (estimated in the tens of billions of pounds worldwide each year). Developing new strategies to combat viral threats is of tremendous importance, as recognized by many organizations including the United Nations, World Health Organization, and UK Government. Most antiviral drugs work through a classical mechanism that involves a 1:1 interaction of the drug with its target. An emerging strategy in Medicinal Chemistry seeks to overcome this "occupancy based" limitation using a new mechanism called protein degradation. There are lots of potential advantages to the protein degradation approach, but its new enough that it hasn't really been explored much in an antiviral context. This project will explore the protein degradation mechanism in targeting 3 viruses of importance to human health: HIV, influenza, and the SARS-CoV-2 virus that is causing the current Covid-19 pandemic. Although we're not aiming to generate a new drug during this project period (that takes longer and costs more), we believe that this project will lay the groundwork for important new therapies in the future. There's no doubt that these therapies will be needed, as viruses are constantly developing resistance.

Publications

10 25 50
 
Description One early objective of the grant (related to HIV capsid) proved more challenging than envisaged. A workaround is in progress, as is progress on other areas of the grant.
Exploitation Route Knowledge from our publication will help others understand how a widely studied compound (Pf74) interacts with its viral target (HIV capsid).
Sectors Chemicals

Healthcare

 
Description I am a co-inventor on a patent application (PCT/EP2024/070595) in collaboration with Dr. Leo James at the LMB in Cambridge, with an accompanying revenue sharing agreement to UofG. The IP in this patent forms the basis for a spin-out company (TrimTech Therapeutics) based in Cambridge. The underpinning science behind this work is using small organic molecules to engage a protein called Trim21. My contribution was to design both the structures and synthetic routes to prepare the compounds that form the basis of the patent. Dr. James is the world's expert on Trim21, and led the biological studies that demonstrated the effectiveness of these compounds. Due to the highly commercially sensitive nature of this work, our results are unpublished. (The patent was filed in late 2024.) We expect to publish this work in 2025.
First Year Of Impact 2022
Sector Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description Collaboration with Dr. Leo James 
Organisation Medical Research Council (MRC)
Department MRC Laboratory of Molecular Biology (LMB)
Country United Kingdom 
Sector Academic/University 
PI Contribution Our interest is from the chemical perspective - building the small molecules envisioned to have the planned biological effect. We have contributed in terms of designing synthetic routes and generating new compounds for testing.
Collaborator Contribution Dr. James' lab are the world leaders on a particular piece of cellular machinery that functions naturally to degrade foreign pathogens. We have engaged with them to try to "hijack" this machinery and force it to recognise disease-relevant targets that were otherwise untouched.
Impact Patent application submitted PCT/EP2024/070595 Multidisciplinary: Chemistry, Cellular Biology Publication to follow, probably in 2025
Start Year 2021
 
Description Pint-of-Science (Glasgow) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact An informal talk followed by QnA session. The talk was aimed at a general audience. Ca. 30 people of various backgrounds attended. Quite good engagement.
Year(s) Of Engagement Activity 2023
URL https://pintofscience.co.uk/event/the-future-is-healthy