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

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)


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.

Original languageEnglish
Article number3103
Number of pages26
Issue number7
Publication statusPublished - Apr 2023


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

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