Novel HIV-1 Capsid-targeting Small Molecules of the PF74 Binding Site

Overview

Journal Eur J Med Chem

Specialty Chemistry

Date 2020 Aug 20

PMID 32814250

Citations 12

Authors

Lei Wang

Mary C Casey

Sanjeev Kumar V Vernekar

Rajkumar Lalji Sahani

Jayakanth Kankanala

Karen A Kirby

Haijuan Du

Atsuko Hachiya

Huanchun Zhang

Philip R Tedbury

Jiashu Xie

Stefan G Sarafianos

Zhengqiang Wang

Affiliations

Soon will be listed here.

Abstract

The PF74 binding site in HIV-1 capsid protein (CA) is a compelling antiviral drug target. Although PF74 confers mechanistically distinct antiviral phenotypes by competing against host factors for CA binding, it suffers from prohibitively low metabolic stability. Therefore, there has been increasing interest in designing novel sub-chemotypes of PF74 with similar binding mode and improved metabolic stability. We report herein our efforts to explore the inter-domain interacting indole moiety for designing novel CA-targeting small molecules. Our design includes simple substitution on the indole ring, and more importantly, novel sub-chemotypes with the indole moiety replaced with a few less electron-rich rings. All 56 novel analogs were synthesized and evaluated for antiviral activity, cytotoxicity, and impact on CA hexamer stability. Selected analogs were tested for metabolic stability in liver microsomes. Molecular modeling was performed to verify compound binding to the PF74 site. In the end, 5-hydroxyindole analogs (8,9 and 12) showed improved potency (up to 20-fold) over PF74. Of the novel sub-chemotypes, α- and β-naphthyl analogs (33 and 27) exhibited sub micromolar antiviral potencies comparable to that of PF74. Interestingly, although only moderately inhibiting HIV-1 (single-digit micromolar ECs), analogs of the 2-indolone sub-chemotype consistently lowered the melting point (T) of CA hexamers, some with improved metabolic stability over PF74.

Citing Articles

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Uracil derivatives as HIV-1 capsid protein inhibitors: design, , and cytotoxicity studies.

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Structure-based virtual screening workflow to identify antivirals targeting HIV-1 capsid.

Sun Q, Biswas A, Vijayan R, Craveur P, Forli S, Olson A J Comput Aided Mol Des. 2022; 36(3):193-203.

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

Sahani R, Akther T, Cilento M, Castaner A, Zhang H, Kirby K RSC Med Chem. 2022; 12(12):2031-2044.

PMID: 35028563 PMC: 8672819. DOI: 10.1039/d1md00292a.

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