Thursday, November 21, 2024
11/21/2024
Targeted Degradation of HIV Integrase as a Novel Treatment of Infection PROJECT SUMMARY Due to the development of antiretroviral therapy, HIV-1 infection is no longer a death sentence but rather a treatable chronic disease, providing people with HIV an almost normal life expectancy. However, the most recent WHO HIV Drug Resistance Report indicates that the prevalence of acquired and transmitted HIV drug resistance has exponentially increased in the recent years. The prevalence of three and four-class resistant HIV is already estimated to range from 5 to 10% in Europe, while somewhat lower rates are still reported for North America (<3%). Indeed, pan-resistant viruses against some drug classes have already been reported. It seems inevitable that fully drug resistant viruses will arise in the not-too-distant future, which necessitates the development of novel anti-HIV drugs. Rather than continue to design new inhibitors for drug-resistant HIV, we propose an alternative strategy – the development of proteolysis-targeting chimeras (PROTACs) using existing anti-HIV drugs. PROTACs are small, bifunctional molecules that contain a warhead domain specific to the targeted protein of interest coupled by a short linker to an E3 ubiquitin ligase binding domain. Rather than working as a classical inhibitor, these small molecules promote ubiquitination and subsequent proteasomal degradation of the target protein. Using this technique to degrade pathological proteins has the added benefit that PROTACs can often be used at concentrations significantly lower than standard inhibitors, as there is no need for PROTACs to be present at stoichiometric concentrations. Once a PROTAC induces ubiquitination of the target protein, the protein is degraded and the PROTAC is free to bind another protein and repeat the cycle. Of particular importance to this project is that the transient nature of PROTAC interaction with, and subsequent ubiquitination of the target protein means that a high affinity drug-target interaction is not as necessary as with classical stoichiometric inhibitors. Indeed, PROTACs developed for oncogenic kinases using existing inhibitors as the warhead domain were able to induce degradation of kinases with mutations that conferred resistance to the same inhibitors. We postulate that it will be possible to target HIV proteins in virus that has become resistant to the inhibitory effect of a drug with the corresponding PROTAC, due to the lower binding affinity required for degradation compared to inhibition. Our early stage PROTACs designed to induce degradation of the HIV integrase enzyme show nanomolar efficacy in both proteolysis of integrase, as well as a blockade of de novo HIV infection in T cells using well-established assays. This application combines the expertise of investigators in PROTAC design and biological assay development with that of an established research team at an NIH CFAR site. Our goal is the development of proof-of-principle PROTACs that test the hypothesis that PROTACs are active against viruses that have developed resistance mutations in the viral protein that is targeted by the PROTAC warhead. As expected for an R21 application, this is a high-risk proposal; but if successful, the outcome will provide new avenues for anti-HIV drug development for the increasingly resistant HIV virus.
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