Molecules (Mar 2023)

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

  • Mahta Mansouri,
  • Shawn Rumrill,
  • Shane Dawson,
  • Adam Johnson,
  • Jo-Anne Pinson,
  • Menachem J. Gunzburg,
  • Catherine F. Latham,
  • Nicholas Barlow,
  • George W. Mbogo,
  • Paula Ellenberg,
  • Stephen J. Headey,
  • Nicolas Sluis-Cremer,
  • David Tyssen,
  • Joseph D. Bauman,
  • Francesc X. Ruiz,
  • Eddy Arnold,
  • David K. Chalmers,
  • Gilda Tachedjian

DOI
https://doi.org/10.3390/molecules28073103
Journal volume & issue
Vol. 28, no. 7
p. 3103

Abstract

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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.

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