Project: Designing antivirals that the virus cannot easily escape

Life Sciences Insitute

This project is looking at designing antiviral compounds that target a part of the virus it cannot easily mutate, aiming to create treatments that remain effective even as new variants emerge.

Challenge Space

Health Resistance

Prinicipal Investigator(s) and team names

Dr Darren Fayne, Molecular Design Group, Dr Choon Kim, University of Notre Dame

Collaborating Institutions

Funding support

Project start date

December 2022

End date

Current

Problem

Antiviral drugs fail in much the same way antibiotics do. Most COVID-19 treatments were aimed at the spike protein or the main protease, and spike is the fastest-changing protein the virus has.

Antibody treatments were withdrawn one after another as new variants appeared, and changes that reduce the effect of protease inhibitors have now been described. A drug is only durable if it binds somewhere the virus cannot afford to alter.

Background

One such site is Mac1, part of the nsp3 protein, which removes chemical marks the host immune system places on viral proteins and so helps the virus blunt our early immune response.

Mac1 is similar across coronaviruses and tightly constrained by the chemistry it has to perform, which means changes that would evade a drug also tend to damage the virus.

The group identified it as a target through its own analysis of which parts of SARS-CoV-2 vary least between isolates and entered the international CACHE Challenge #3 on that basis, placing fourth worldwide.

Solution

Two of the compounds predicted by the group were confirmed experimentally as binders in independent enzyme and biophysical testing.

Solubility of the compounds is an issue. Work is now focused on turning those two starting points into a more soluble and potent compound series: establishing exactly how they sit in the site, designing improved versions using pharmacophore tools built in the group, and testing whether improvements hold across the variation seen in sequenced coronavirus genomes, so that potency is gained only at contacts the virus cannot afford to lose.

This phase is supported by a Notre Dame-DCU seed award, in conjunction with Dr Choon Kim, who biologically evaluates the compounds we design.