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Journal article
Design, synthesis, and mechanistic study of 2-piperazineone-bearing peptidomimetics as novel HIV capsid modulators
RSC medicinal chemistry, v 14(7), pp 1272-1295
20 Jul 2023
PMID: 37484571
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
HIV-1 capsid (CA) is an attractive target for its indispensable roles in the viral life cycle. We report the design, synthesis, and mechanistic study of a novel series of 2-piperazineone peptidomimetics as HIV capsid modulators by mimicking the structure of host factors binding to CA. F-Id-3o was the most potent compound from the synthesized series, with an anti-HIV-1 EC
value of 6.0 μM. However, this series of compounds showed a preference for HIV-2 inhibitory activity, in which Id-3o revealed an EC
value of 2.5 μM (anti-HIV-2 potency), an improvement over PF74. Interestingly, F-Id-3o did bind HIV-1 CA monomers and hexamers with comparable affinity, unlike PF74, consequently showing antiviral activity in the early and late stages of the HIV-1 lifecycle. Molecular dynamics simulations shed light on F-Id-3o and Id-3o binding modes within the HIV-1/2 CA protein and provide a possible explanation for the increased anti-HIV-2 potency. Metabolic stability assays in human plasma and human liver microsomes indicated that although F-Id-3o has enhanced metabolic stability over PF74, further optimization is necessary. Moreover, we utilized computational prediction of drug-like properties and metabolic stability of F-Id-3o and PF74, which correlated well with experimentally derived metabolic stability, providing an efficient computational pipeline for future preselection based on metabolic stability prediction. Overall, the 2-piperazineone-bearing peptidomimetics are a promising new chemotype in the CA modulators class with considerable optimization potential.
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Details
- Title
- Design, synthesis, and mechanistic study of 2-piperazineone-bearing peptidomimetics as novel HIV capsid modulators
- Creators
- Xujie Zhang - Shandong UniversityLin Sun - Shandong UniversityShujing Xu - Shandong UniversityTianguang Huang - Shandong UniversityFabao Zhao - Shandong UniversityDang Ding - Shandong UniversityChuanfeng Liu - Shandong UniversityXiangyi Jiang - Shandong UniversityYucen Tao - Shandong UniversityDongwei Kang - Shandong UniversityErik De Clercq - Rega Institute for Medical ResearchChristophe Pannecouque - Rega Institute for Medical ResearchSimon Cocklin - Specifica (United States)Alexej Dick - Drexel UniversityXinyong Liu - Shandong UniversityPeng Zhan - Shandong University
- Publication Details
- RSC medicinal chemistry, v 14(7), pp 1272-1295
- Publisher
- Royal Society of Chemistry
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:001000409700001
- Scopus ID
- 2-s2.0-85162128926
- Other Identifier
- 991021230007704721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Medicinal