Project: Targeting the parts of a virus that cannot change

Challenge Space

Health - Resistance

Prinicipal Investigator(s) and team names

Dr Darren Fayne, Molecular Design Group

Collaborating Institutions

Funding support

Project start date

June 2022

End date

Current

Problem 

Resistance appears when a drug depends on part of a protein the pathogen can afford to alter. It has happened for hepatitis C, influenza and SARS-CoV-2 treatments alike, and resistance testing is now part of routine clinical guidance. 

Most computational drug discovery does not consider this: a compound is scored against a single fixed protein structure, with no consideration of whether the parts it relies on are the same in the strains a patient is likely to carry.

Background

The group takes the opposite starting point, asking first which parts of a viral protein are unchanged across every sequenced isolate and only then looking for compounds that bind there. Applying this to the non-structural proteins of SARS-CoV-2 and hepatitis C identified nsp13, the viral helicase, as conserved and largely unexploited. 

The helicase is the motor that unwinds the virus's genetic material so it can be copied, and the tunnel through which that material passes is one of the least variable features of the virus. On the strength of that analysis the group entered the international CACHE Challenge #2 against the tunnel and was ranked third in the world.

Solution

Independent testing identified two compounds that bind the site. Both bind weakly, and both are poorly soluble in water, which has limited the assays available to characterise them further. Neither is a reason to stop. Weak binding is the normal starting condition for a small molecule at a difficult site, and poor solubility is usually a fixable property rather than a fundamental one, reflecting a molecule that is too flat or too greasy rather than one that binds in the wrong place. 

The current work is progressing both compounds on that basis: simulation of how each sits in the tunnel is being used to separate the parts of the molecule the protein actually grips from those free to be altered, so that polar groups can be added where they will improve solubility without disturbing the interaction. Improved compounds return for binding and enzyme testing, and every modification is checked against the conservation analysis that selected the site, so that the series stays anchored to features the virus cannot readily change.