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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2023-03, Vol.28 (7), p.3103
• Main Authors: Mansouri, Mahta, Rumrill, Shawn, Dawson, Shane, Johnson, Adam, Pinson, Jo-Anne, Gunzburg, Menachem J, Latham, Catherine F, Barlow, Nicholas, Mbogo, George W, Ellenberg, Paula, Headey, Stephen J, Sluis-Cremer, Nicolas, Tyssen, David, Bauman, Joseph D, Ruiz, Francesc X, Arnold, Eddy, Chalmers, David K, Tachedjian, Gilda
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; Acquired Immunodeficiency Syndrome - drug therapy; AIDS; Anti-HIV Agents - pharmacology; Anti-HIV Agents - therapeutic use; Binding; Binding sites; Care and treatment; Drug discovery; Drug resistance; Drug therapy; Enzymes; FDA approval; fragment-based drug design; Genomes; Health aspects; HIV; HIV infection; HIV Reverse Transcriptase; HIV-1; Human immunodeficiency virus; Humans; Immune system; Immunosuppressive agents; Lead compounds; Methods; non-nucleoside reverse transcriptase inhibitors (NNRTIs); Organic compounds; Physiological aspects; Replication; Reverse transcriptase; Reverse Transcriptase Inhibitors - chemistry; RNA-directed DNA polymerase; Solvents; Vectors
• ISSN: 1420-3049; 1420-3049
• 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 ), 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 -a minimal but efficient NNRTI-offering a starting site for the development of novel dual NNIBP-Adjacent site inhibitors.