Toward HIV-1 CA-targeting antivirals: an emerging paradigm
Zhengqiang Wang, PhD
Center for Drug Design, University of Minnesota, United States of America
Lei Wang a, Sanjeev Kumar V. Vernekar a, Rajkumar Lalji Sahani a, Jayakanth Kankanala a
Jiashu Xie a, Mary C. Casey b, Haijuan Du c, Huanchun Zhang c, Atsuko Hachiya d, Philip R. Tedbury c, Karen A. Kirby c, Stefan G. Sarafianos b,c, and Zhengqiang Wang* a
a Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA
b Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Christopher S. Bond Life Sciences Center, Columbia, MO 65211, USA
c Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
d Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi, 460-0001, Japan.
The capsid protein (CA) of HIV-1 plays important roles in both late and early steps of the viral replication cycle. CA-CA interactions drive the assembly of viral capsids. CA also interacts with various host factors to facilitate multiple post-entry events, such as uncoating, reverse transcription, nuclear entry and site of integration. Of reported HIV-1 CA-targeting chemotypes, the peptidomimetic PF-74 is particularly well characterized. PF-74 binds to a well-defined pocket at the CA-CA interface between the CANTD and the CACTD of adjacent monomers. This same pocket is used by a few important host factors, such as Nup153 and CPSF6. Therefore, compounds targeting this pocket are especially valuable in developing novel antivirals and probing the molecular basis of CA-host factor interactions. We present herein our medicinal chemistry efforts on the design and characterization of a few different chemotypes targeting the PF-74 binding pocket. First, we conducted a comprehensive chemical profiling of PF-74 via structure-guided analogue synthesis and structure-activity relationship (SAR). Second, we designed and synthesized novel CA inhibitor types by altering the backbone of PF-74 via scaffold hybridization or conformational constraint. Third, we pursued a pharmacophore search using the CA / PF-74 co- crystal structure. All newly synthesized compounds were assayed for binding to CA hexamers, antiviral potency and cytotoxicity. Overall, these efforts identified novel and potent HIV-1 CA- targeting small molecules.
The International Society for Antiviral Research (ISAR) is an internationally recognized organization for scientists involved in basic, applied, and clinical aspects of antiviral research. The Society main event is the annual International Conference on Antiviral Research (ICAR), a truly interdisciplinary meeting which attracts the interest of chemists, biologists, and clinicians.