期刊
FRONTIERS IN MICROBIOLOGY
卷 10, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fmicb.2019.01227
关键词
human immunodeficiency virus; capsid; assembly; small molecules; inhibitors; disassembly; uncoating
类别
资金
- Swedish Research Council [201701330, 2016-01675]
- Stockholm Count Council [ALF 20160074]
- National Institute of Health [R21AI127195]
- Bond Life Sciences Center grant [DU108]
- Mizzou Advantage grant [DKE13]
- Swedish Research Council [2016-01675] Funding Source: Swedish Research Council
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 similar to 7-fold better affinity than well-studied capsid inhibitor PF74, suggesting that it can be developed as a possible CA inhibitor.
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