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Toward Structurally Novel and Metabolically Stable HIV-1 Capsid-Targeting Small Molecules

Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA
Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Christopher S. Bond Life Sciences Center, Columbia, MO 65211, USA
Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
Author to whom correspondence should be addressed.
These authors contributed equally.
Viruses 2020, 12(4), 452;
Received: 30 March 2020 / Revised: 11 April 2020 / Accepted: 14 April 2020 / Published: 16 April 2020
(This article belongs to the Special Issue Antiretroviral Drug Development and HIV Cure Research)
HIV-1 capsid protein (CA) plays an important role in many steps of viral replication and represents an appealing antiviral target. Several CA-targeting small molecules of various chemotypes have been studied, but the peptidomimetic PF74 has drawn particular interest due to its potent antiviral activity, well-characterized binding mode, and unique mechanism of action. Importantly, PF74 competes against important host factors for binding, conferring highly desirable antiviral phenotypes. However, further development of PF74 is hindered by its prohibitively poor metabolic stability, which necessitates the search for structurally novel and metabolically stable chemotypes. We have conducted a pharmacophore-based shape similarity search for compounds mimicking PF74. We report herein the analog synthesis and structure-activity relationship (SAR) of two hits from the search, and a third hit designed via molecular hybridization. All analogs were characterized for their effect on CA hexamer stability, antiviral activity, and cytotoxicity. These assays identified three active compounds that moderately stabilize CA hexamer and inhibit HIV-1. The most potent analog (10) inhibited HIV-1 comparably to PF74 but demonstrated drastically improved metabolic stability in liver microsomes (31 min vs. 0.7 min t1/2). Collectively, the current studies identified a structurally novel and metabolically stable PF74-like chemotype for targeting HIV-1 CA. View Full-Text
Keywords: HIV-1; capsid-targeting antivirals; PF74; metabolic stability HIV-1; capsid-targeting antivirals; PF74; metabolic stability
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MDPI and ACS Style

Vernekar, S.K.V.; Sahani, R.L.; Casey, M.C.; Kankanala, J.; Wang, L.; Kirby, K.A.; Du, H.; Zhang, H.; Tedbury, P.R.; Xie, J.; Sarafianos, S.G.; Wang, Z. Toward Structurally Novel and Metabolically Stable HIV-1 Capsid-Targeting Small Molecules. Viruses 2020, 12, 452.

AMA Style

Vernekar SKV, Sahani RL, Casey MC, Kankanala J, Wang L, Kirby KA, Du H, Zhang H, Tedbury PR, Xie J, Sarafianos SG, Wang Z. Toward Structurally Novel and Metabolically Stable HIV-1 Capsid-Targeting Small Molecules. Viruses. 2020; 12(4):452.

Chicago/Turabian Style

Vernekar, Sanjeev Kumar V., Rajkumar Lalji Sahani, Mary C. Casey, Jayakanth Kankanala, Lei Wang, Karen A. Kirby, Haijuan Du, Huanchun Zhang, Philip R. Tedbury, Jiashu Xie, Stefan G. Sarafianos, and Zhengqiang Wang. 2020. "Toward Structurally Novel and Metabolically Stable HIV-1 Capsid-Targeting Small Molecules" Viruses 12, no. 4: 452.

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