Discovery of Novel 1,2,4-triazole Phenylalanine Derivatives Targeting an Unexplored Region Within the Interprotomer Pocket of the HIV Capsid Protein

Overview

Journal J Med Virol

Specialty Microbiology

Date 2022 Aug 10

PMID 35949003

Authors

Xiangyi Jiang

Prem Prakash Sharma

Brijesh Rathi

Xiangkai Ji

Lide Hu

Zhen Gao

Dongwei Kang

Zhao Wang

Minghui Xie

Shujing Xu

Xujie Zhang

Erik De Clercq

Simon Cocklin

Christophe Pannecouque

Alexej Dick

Xinyong Liu

Peng Zhan

Affiliations

Soon will be listed here.

Abstract

Human immunodeficiency virus (HIV) capsid (CA) protein is a promising target for developing novel anti-HIV drugs. Starting from highly anticipated CA inhibitors PF-74, we used scaffold hopping strategy to design a series of novel 1,2,4-triazole phenylalanine derivatives by targeting an unexplored region composed of residues 106-109 in HIV-1 CA hexamer. Compound d19 displayed excellent antiretroviral potency against HIV-1 and HIV-2 strains with EC values of 0.59 and 2.69 µM, respectively. Additionally, we show via surface plasmon resonance (SPR) spectrometry that d19 preferentially interacts with the hexameric form of CA, with a significantly improved hexamer/monomer specificity ratio (ratio = 59) than PF-74 (ratio = 21). Moreover, we show via SPR that d19 competes with CPSF-6 for binding to CA hexamers with IC value of 33.4 nM. Like PF-74, d19 inhibits the replication of HIV-1 NL4.3 pseudo typed virus in both early and late stages. In addition, molecular docking and molecular dynamics simulations provide binding mode information of d19 to HIV-1 CA and rationale for improved affinity and potency over PF-74. Overall, the lead compound d19 displays a distinct chemotype form PF-74, improved CA affinity, and anti-HIV potency.

Citing Articles

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Discovery, Crystallographic Studies, and Mechanistic Investigations of Novel Phenylalanine Derivatives Bearing a Quinazolin-4-one Scaffold as Potent HIV Capsid Modulators.

Xu S, Sun L, Barnett M, Zhang X, Ding D, Gattu A J Med Chem. 2023; 66(23):16303-16329.

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Design, Synthesis and Structure-Activity Relationships of Phenylalanine-Containing Peptidomimetics as Novel HIV-1 Capsid Binders Based on Ugi Four-Component Reaction.

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