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

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Singh K, Gallazzi F, Hill KJ, Burke DH, Lange MJ, Quinn TP, Neogi U, Sonnerborg A

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

Front Microbiol. 2019 Jun 20;10:1227. doi: 10.3389/fmicb.2019.01227. eCollection 2019.

PubMed ID

31312185 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drugs

Lenacapavir

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Lenacapavir	Gag-Pol polyprotein	Protein		Yes	Inhibitor	Details