Novel inhibitor binding site discovery on HIV-1 capsid N-terminal domain by NMR and X-ray crystallography.
Related Articles Novel inhibitor binding site discovery on HIV-1 capsid N-terminal domain by NMR and X-ray crystallography.
ACS Chem Biol. 2013 Mar 15;
Authors: Goudreau N, Lemke CT, Faucher AM, Grand-Maître C, Goulet S, Lacoste JE, Rancourt J, Malenfant E, Mercier JF, Titolo S, Mason SW
Abstract
The HIV-1 capsid (CA) protein, a domain of Gag, which participates in formation of both the mature and immature capsid, represents a potential target for antiviral drug development. Characterization of hits obtained via high throughput screening of an in vitro capsid assembly assay led to multiple compounds having this potential. We previously presented the characterization of two inhibitor series that bind the N-terminal domain of the capsid (CANTD), at a site located at the bottom of its helical bundle, often referred to as the CAP-1 binding site. In this work we characterize a novel series of benzimidazole hits. Initial optimization of this series led to compounds with improved in vitro assembly and antiviral activity. Using NMR spectroscopy we found that this series binds to a unique site on CANTD, located at the apex of the helical bundle, well removed from previously characterized binding sites for CA inhibitors. 2D 1H-15N HSQC and 19F-NMR showed that binding of the benzimidazoles to this distinct site does not affect the binding of either cyclophilin A (CypA) to the CypA-binding loop or a benzodiazepine-based CA assembly inhibitor to the CAP-1 site. Unfortunately, while compounds of this series achieved promising in vitro assembly and antiviral effects, they also were found to be quite sensitive to a number of naturally occurring CANTD polymorphisms observed among clinical isolates. Despite the negative impact of this finding for drug development, the discovery of multiple inhibitor binding sites on CANTD shows that capsid assembly is much more complex than previously realized.
PMID: 23496828 [PubMed - as supplied by publisher]
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