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

Molecules. 2023 Mar 30;28(7):3103. doi: 10.3390/molecules28073103.


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.

MeSH terms

  • Acquired Immunodeficiency Syndrome* / drug therapy
  • Anti-HIV Agents* / pharmacology
  • Anti-HIV Agents* / therapeutic use
  • HIV Reverse Transcriptase
  • HIV-1*
  • Humans
  • Reverse Transcriptase Inhibitors / chemistry


  • reverse transcriptase, Human immunodeficiency virus 1
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase
  • Anti-HIV Agents