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Journal article
Discovery of novel 1,2,4‐triazole phenylalanine derivatives targeting an unexplored region within the interprotomer pocket of the HIV capsid protein
Journal of medical virology, v 94(12), pp 5975-5986
Dec 2022
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 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.
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Details
- Title
- Discovery of novel 1,2,4‐triazole phenylalanine derivatives targeting an unexplored region within the interprotomer pocket of the HIV capsid protein
- Creators
- Xiangyi Jiang - Shandong UniversityPrem 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 UniversityLide Hu - Shandong UniversityZhen Gao - Shandong UniversityDongwei Kang - Shandong UniversityZhao Wang - Shandong UniversityMinghui Xie - Shandong UniversityShujing Xu - Shandong UniversityXujie Zhang - Shandong UniversityErik De Clercq - Rega Institute for Medical ResearchSimon Cocklin - Drexel UniversityChristophe Pannecouque - Rega Institute for Medical ResearchAlexej Dick - Drexel UniversityXinyong Liu - Shandong UniversityPeng Zhan - Shandong University
- Publication Details
- Journal of medical virology, v 94(12), pp 5975-5986
- Publisher
- Wiley
- Number of pages
- 12
- Grant note
- 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)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000842178600001
- Scopus ID
- 2-s2.0-85135962727
- Other Identifier
- 991019167466204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Virology