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Targeting novel sites on reverse transcriptase for HIV treatment and prevention

Human immunodeficiency virus (HIV) remains a global public health threat. In 2021 there was an estimated 38.4 million people living with HIV, 1.5 million new HIV infections, and 650,000 people died from an AIDS-related illness. Antiretroviral therapy (ART) has had a dramatic impact on the natural history of HIV. In 2020, around 28.7 million people were accessing therapy. 

However, cessation of ART results in virus rebound and thus therapy is lifelong. Life-long ART can lead to drug resistance, toxicity, intolerance and exhaustion of drug options for both HIV treatment and prevention. There are no approved drugs for curing HIV.  New drug classes are needed to control HIV infection in heavily-treatment experienced (THE) individuals.

Our overall aim is to characterise new drug scaffolds and their novel binding sites on HIV reverse transcriptase to discover chemical building blocks of a new HIV drug class. This new drug class is intended to have a distinct mechanism of action and resistance profile to drugs currently used for HIV treatment and prevention and in the pipeline.

To identify a novel HIV-1 drug class we used fragment-based drug screening to identify building blocks of drugs that bind to HIV-1 reverse transcriptase. We identified fragments that have a distinct mechanism of action and similar potency in inhibiting wild-type and drug-resistant HIV-1 reverse transcriptase. Co-crystal structures of related fragments with HIV-1 reverse transcriptase show that they bind to a new site on the enzyme. We have elaborated these fragments into larger molecules that inhibit wild-type and drug resistant HIV-1 RT in the low micromolar range and retain similar mechanism of action as the initial fragments.

We are evaluating the ability of these molecules to inhibit a panel of drug resistant reverse transcriptase mutants and with our collaborators employing strategies to visualize where these molecules bind to the reverse transcriptase to elaborate into more potent inhibitors.

Professor Gilda Tachedjian

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Funding
Partners

  • NHMRC
  • BioCurate

Partners +
Collaborators

  • Associate Professor David Chalmers
  • Professor David Thal
  • Professor Nicolas Sluis-Cremer
  • Professor Eddy Arnold
  • Associate Professor James McMahon

Project
Team

Meet the project team. Together, we are translating research into better health, for all.

Publications

VIEW ALL RESEARCH
Targeting HIV-1 reverse transcriptase using a fragment-based approach.

Mansouri M, Rumrill S, Dawson S, Johnson A, Pinson JA, Gunzburg MJ, Latham CF, Barlow N, Mbogo GW, Ellenberg P, Headey SJ, Sluis-Cremer N, Tyssen D, Bauman JD, Ruiz FX, Arnold E, Chalmers DK, Tachedjian G

  • 03 Mar 2023
HIV + AIDS
Fragment Based Strategies for Discovery of Novel HIV-1 Reverse Transcriptase and Integrase Inhibitors.

Latham CF, La J, Tinetti RN, Chalmers DK, Tachedjian G

  • Current topics in medicinal chemistry
  • 03 Nov 2016
Identification of mechanistically distinct inhibitors of HIV-1 reverse transcriptase through fragment screening.

La J, Latham CF, Tinetti RN, Johnson A, Tyssen D, Huber KD, Sluis-Cremer N, Simpson JS, Headey SJ, Chalmers DK, Tachedjian G

  • Proceedings of the National Academy of Sciences of the United States of America
  • 18 May 2015