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GS-CA Compounds: First-In-Class HIV-1 Capsid Inhibitors Covering Multiple Grounds

GS-CA Compounds: First-In-Class HIV-1 Capsid Inhibitors Covering Multiple Grounds

Kamal Singh, Fabio Gallazzi, Kyle J Hill, Donald H Burke, Margaret J Lange, Thomas P Quinn, Ujjwal Neogi, Anders Sönnerborg

Front Microbiol. 2019 Jun 20;10:1227.

PMID: 31312185

Abstract:

Recently reported HIV-1 capsid (CA) inhibitors GS-CA1 and GS-6207 (an analog of GS-CA1) are first-in-class compounds with long-acting potential. Reportedly, both compounds have greater potency than currently approved anti-HIV drugs. Due to the limited access to experimental data and the compounds themselves, a detailed mechanism of their inhibition is yet to be delineated. Using crystal structures of capsid-hexamers bound to well-studied capsid inhibitor PF74 and molecular modeling, we predict that GS-CA compounds bind in the pocket that is shared by previously reported CA inhibitors and host factors. Additionally, comparative modeling suggests that GS-CA compounds have unique structural features contributing to interactions with capsid. To test their proposed binding mode, we also report the design of a cyclic peptide combining structural units from GS-CA compounds, host factors, and previously reported capsid inhibitors. This peptide (Pep-1) binds CA-hexamer with a docking score comparable to GS-CA compounds. Affinity determination by MicroScale thermophoresis (MST) assays showed that CA binds Pep-1 with a ~7-fold better affinity than well-studied capsid inhibitor PF74, suggesting that it can be developed as a possible CA inhibitor.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1352879652	PF74		1352879-65-2	Price

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