Discovery of a new drug class for HIV treatment and prevention

There is a real threat that drug resistance, toxicity and intolerance will eventually lead to exhaustion of antiretroviral drug options for both HIV treatment and prevention. There is little in the way of new drug classes in the pipeline and the same drug classes are being used for HIV treatment and prevention.

We have initiated a drug discovery program targeting HIV-1 reverse transcriptase (RT) to identify compounds that inhibit this essential enzyme and validated drug target. We are using an innovative and a validated paradigm for drug discovery called fragment-based drug design that uses very small compounds called ‘fragments’ to find inhibitors with novel mechanisms of action against HIV-1 RT.

Our screens have discovered fragments with mechanisms that are distinct to other drugs that inhibit HIV-1 RT in the clinic (La et al, 2015 PNAS 112:6979) and some of these have been progressed to molecules that have low micro molar activity against wild-type and drug-resistant RT (Mansouri et al 2023 Molecules 28:3103). Our data strongly suggests that our advanced molecules are unlikely to bind to the same site as RT drug classes used in the clinic although the exact binding site for these molecules remains to be elucidated.

The aim of this study is to further characterize the inhibitory activity of our compounds including employing and use site directed mutagenesis to alter residues in a previously defined pocket in the HIV RT to determine if our advanced molecules bind to this site. Techniques will include molecular biology, cloning, mutagenesis, expression and purification of RT protein, SDS-PAGE, and RT enzyme assays. This study will underpin the development of a novel class of RT inhibitor for use in HIV-1 treatment and prevention. 

This is a joint project between the Tachedjian Lab and Monash Institute of Pharmaceutical Sciences with Dr David Chalmers.