Targeting HIV-1 Reverse Transcriptase Using a Fragment-Based Approach

  • Molecules. 2023 Mar 30;28(7):3103. doi: 10.3390/molecules28073103.
Mahta Mansouri  1 ,  Shawn Rumrill  2 ,  Shane Dawson  1 ,  Adam Johnson  3 ,  Jo-Anne Pinson  1 ,  Menachem J Gunzburg  1 ,  Catherine F Latham  3 ,  Nicholas Barlow  1 ,  George W Mbogo  3 ,  Paula Ellenberg  3 ,  Stephen J Headey  1 ,  Nicolas Sluis-Cremer  4 ,  David Tyssen  3 ,  Joseph D Bauman  2 ,  Francesc X Ruiz  2 ,  Eddy Arnold  2 ,  David K Chalmers  1 ,  Gilda Tachedjian  3  5  6
Affiliations
  • 1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
  • 2. Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
  • 3. Retroviral Biology and Antivirals Laboratory, Disease Elimination Program, Life Sciences Discipline, Burnet Institute, Melbourne, VIC 3004, Australia.
  • 4. Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
  • 5. Department of Microbiology, Monash University, Clayton, VIC 3168, Australia.
  • 6. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
PMID: 37049868 DOI: 10.3390/molecules28073103
Abstract

Human immunodeficiency virus type I (HIV-1) is a retrovirus that infects cells of the host's immune system leading to acquired immunodeficiency syndrome and potentially death. Although treatments are available to prevent its progression, HIV-1 remains a major burden on health resources worldwide. Continued emergence of drug-resistance mutations drives the need for novel drugs that can inhibit HIV-1 replication through new pathways. The viral protein Reverse Transcriptase (RT) plays a fundamental role in the HIV-1 replication cycle, and multiple approved medications target this enzyme. In this study, fragment-based drug discovery was used to optimize a previously identified hit fragment (compound B-1), which bound RT at a novel site. Three series of compounds were synthesized and evaluated for their HIV-1 RT binding and inhibition. These series were designed to investigate different vectors around the initial hit in an attempt to improve inhibitory activity against RT. Our results show that the 4-position of the core scaffold is important for binding of the fragment to RT, and a lead compound with a cyclopropyl substitution was selected and further investigated. Requirements for binding to the NNRTI-binding pocket (NNIBP) and a novel adjacent site were investigated, with lead compound 27-a minimal but efficient NNRTI-offering a starting site for the development of novel dual NNIBP-Adjacent site inhibitors.

Keywords
HIV-1; drug discovery; fragment-based drug design; non-nucleoside reverse transcriptase inhibitors (NNRTIs); reverse transcriptase.
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