Discovery of novel 1,2,4‐triazole phenylalanine derivatives targeting an unexplored region within the interprotomer pocket of the HIV capsid protein

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

doi:10.1002/jmv.28064

Discovery of novel 1,2,4‐triazole phenylalanine derivatives targeting an unexplored region within the interprotomer pocket of the HIV capsid protein

Xiangyi Jiang, Prem Prakash Sharma, Brijesh Rathi, Xiangkai Ji, Lide Hu, Zhen Gao, Dongwei Kang, Zhao Wang, Minghui Xie, Shujing Xu, …

Journal of medical virology, v 94(12), pp 5975-5986

Dec 2022

: https://doi.org/10.1002/jmv.28064

(1)

url

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10790228

Accepted (AM)

capsid inhibitor

HIV‐1

phenylalanine derivatives

scaffold hopping

target‐based drug design

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 EC50 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 IC50 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.

: Discovery of novel 1,2,4‐triazole phenylalanine derivatives targeting an unexplored region within the interprotomer pocket of the HIV capsid protein
: Xiangyi Jiang - Shandong University
Prem Prakash Sharma - Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College, University of Delhi, Delhi, 110007, India.
Brijesh Rathi - Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College, University of Delhi, Delhi, 110007, India.
Xiangkai Ji - Shandong University
Lide Hu - Shandong University
Zhen Gao - Shandong University
Dongwei Kang - Shandong University
Zhao Wang - Shandong University
Minghui Xie - Shandong University
Shujing Xu - Shandong University
Xujie Zhang - Shandong University
Erik De Clercq - Rega Institute for Medical Research
Simon Cocklin - Drexel University
Christophe Pannecouque - Rega Institute for Medical Research
Alexej Dick - Drexel University
Xinyong Liu - Shandong University
Peng Zhan - Shandong University
: Journal of medical virology, v 94(12), pp 5975-5986
: Wiley
: 12
: The Key Project of NSFC for International Cooperation (81420108027) The Science Foundation for Outstanding Young Scholars of Shandong Province (ZR2020JQ31) The Shandong Provincial Key Research and Development Project (2019JZZY021011) NIH/NIAID (R01AI150491) National Natural Science Foundation of China (NSFC) (82173677; 81773574)
: Journal article
: English
: Biochemistry and Molecular Biology
: WOS:000842178600001
: 2-s2.0-85135962727
: 991019167466204721

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