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Journal article
Discovery, Crystallographic Studies, and Mechanistic Investigations of Novel Phenylalanine Derivatives Bearing a Quinazolin-4-one Scaffold as Potent HIV Capsid Modulators
Journal of medicinal chemistry, v 66(23), pp 16303-16329
14 Dec 2023
PMID: 38054267
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Optimization of compound 11L led to the identification of novel HIV capsid modulators, quinazolin-4-one-bearing phenylalanine derivatives, displaying potent antiviral activities against both HIV-1 and HIV-2. Notably, derivatives
and
showed significant improvements, with 2.5-fold over 11L and 7.3-fold over PF74 for HIV-1, and approximately 40-fold over PF74 for HIV-2. The X-ray co-crystal structures confirmed the multiple pocket occupation of
and
in the binding site. Mechanistic studies revealed a dual-stage inhibition profile, where the compounds disrupted capsid-host factor interactions at the early stage and promoted capsid misassembly at the late stage. Remarkably,
and
significantly promoted capsid misassembly, outperforming 11L, PF74, and LEN. The substitution of easily metabolized amide bond with quinolin-4-one marginally enhanced the stability of
in human liver microsomes compared to controls. Overall,
and
highlight their potential as potent HIV capsid modulators, paving the way for future advancements in anti-HIV drug design.
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Details
- Title
- Discovery, Crystallographic Studies, and Mechanistic Investigations of Novel Phenylalanine Derivatives Bearing a Quinazolin-4-one Scaffold as Potent HIV Capsid Modulators
- Creators
- Shujing Xu - Shandong UniversityLin Sun - Shandong UniversityMichael Barnett - University of AucklandXujie Zhang - Shandong UniversityDang Ding - Shandong UniversityAnushka Gattu - Drexel UniversityDazhou Shi - Shandong UniversityJamie R H Taka - University of AucklandWenli Shen - Shandong UniversityXiangyi Jiang - Shandong UniversitySimon Cocklin - Specifica (United States)Erik De Clercq - Rega Institute for Medical ResearchChristophe Pannecouque - Rega Institute for Medical ResearchDavid C Goldstone - University of AucklandXinyong Liu - Shandong UniversityAlexej Dick - Drexel UniversityPeng Zhan - Shandong University
- Publication Details
- Journal of medicinal chemistry, v 66(23), pp 16303-16329
- Publisher
- American Chemical Society (ACS)
- Grant note
- R01 AI150491 / NIAID NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:001125266800001
- Scopus ID
- 2-s2.0-85180013109
- Other Identifier
- 991021811910904721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal