Potency and metabolic stability: a molecular hybrid case in the design of novel PF74-like small molecules targeting HIV-1 capsid protein

Rajkumar Lalji Sahani, Thamina Akther, Maria E. Cilento, Andres Emanuelli Castaner, Huanchun Zhang, Karen A. Kirby, Jiashu Xie, Stefan G. Sarafianos, Zhengqiang Wang

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Abstract

PF74 (1) is a potent and well-characterized prototypical small molecule targeting human immunodeficiency virus type 1 (HIV-1) capsid protein (CA), but not a viable antiviral lead due to the lack of metabolic stability. We report herein our molecular hybridization-based medicinal chemistry efforts toward potent and metabolically stable PF74-like small molecules. The design of the new sub-chemotype4rationally combines binding features of two recently reported PF74-like compounds2and3. The subsequent confirmation and structure-activity relationship (SAR) of hit4aentailed the chemical synthesis of 37 novel analogs, most of which showed modest but meaningful thermal shift, and low μM antiviral activity. The most potent analogs (4a,4d,4o, and4r) all exhibited noticeably improved metabolic stability over PF74. Molecular modeling suggests that these new analogs bind to the PF74 binding site. Overall, our work demonstrated that the molecular hybridization approach is suitable for designing compounds with balanced potency and metabolic stability.

Original languageEnglish (US)
Pages (from-to)2031-2044
Number of pages14
JournalRSC Medicinal Chemistry
Volume12
Issue number12
DOIs
StatePublished - Dec 2021

Bibliographical note

Funding Information:
This research was supported by the National Institute of Allergy and Infectious Diseases, the National Institutes of Health, grant R01AI120860 (to S. G. S. and Z. W.) and F31AI155158 (to M. E. C.). S. G. S. acknowledges funding from the Nahmias-Schinazi Distinguished Chair in Research. We thank the Minnesota Supercomputing Institute for molecular modeling resources.

Publisher Copyright:
© The Royal Society of Chemistry 2021.

PubMed: MeSH publication types

  • Journal Article

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