Open AccessArticle
Targeting HIV-1 Reverse Transcriptase Using a Fragment-Based Approach
by
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 and Gilda Tachedjian
Cited by 3 | Viewed by 4064
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
[...] Read more.
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.
Full article
►▼
Show Figures
