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Journal article
Design, synthesis, and mechanism study of dimerized phenylalanine derivatives as novel HIV-1 capsid inhibitors
European journal of medicinal chemistry, v 226, pp 113848-113848
15 Dec 2021
PMID: 34592608
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
HIV-1 capsid (CA) plays indispensable and multiple roles in the life cycle of HIV-1, become an attractive target in antiviral therapy. Herein, we report the design, synthesis, and mechanism study of a novel series of dimerized phenylalanine derivatives as HIV-1 capsid inhibitors using 2-piperazineone or 2,5-piperazinedione as a linker. The structure-activity relationship (SAR) indicated that dimerized phenylalanines were more potent than monomers of the same chemotype. Further, the inclusion of fluorine substituted phenylalanine and methoxyl substituted aniline was found to be beneficial for antiviral activity. From the synthesized series, Q-c4 was found to be the most potent compound with an EC50 value of 0.57 mu M, comparable to PF74. Interestingly, Q-c4 demonstrated a slightly higher affinity to the CA monomer than the CA hexamer, commensurate with its more significant effect in the late-stage of the HIV-1 lifecycle. Competitive SPR experiments with peptides from CPSF6 and NUP153 revealed that Q-c4 binds to the interprotomer pocket of hexameric CA as designed. Single-round infection assays showed that Q-c4 interferes with the HIV-1 life cycle in a dual-stage manner, affecting both pre-and post-integration. Stability assays in human plasma and human liver microsomes indicated that although Q-c4 has improved stability over PF74, this kind of inhibitor still requires further optimization. And the results of the online molinspiration software predicted that Q-c4 has desirable physicochemical properties but some properties still have some violation from the Lipinski rule of five. Overall, the dimerized phenylalanines are promising novel platforms for developing future HIV-1 CA inhibitors with considerable potential for optimization. (C) 2021 Elsevier Masson SAS. All rights reserved.
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Details
- Title
- Design, synthesis, and mechanism study of dimerized phenylalanine derivatives as novel HIV-1 capsid inhibitors
- Creators
- Xujie Zhang - Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road,250012, Jinan, Shandong, PR China.Lin Sun - Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road,250012, Jinan, Shandong, PR China.Megan E. Meuser - Drexel UniversityWaleed A. Zalloum - American University of MadabaShujing Xu - Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road,250012, Jinan, Shandong, PR China.Tianguang Huang - Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road,250012, Jinan, Shandong, PR China.Srinivasulu Cherukupalli - Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road,250012, Jinan, Shandong, PR China.Xiangyi Jiang - Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road,250012, Jinan, Shandong, PR China.Xiao Ding - Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road,250012, Jinan, Shandong, PR China.Yucen Tao - Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road,250012, Jinan, Shandong, PR China.Dongwei Kang - Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road,250012, Jinan, Shandong, PR China.Erik De Clercq - Rega Institute for Medical ResearchChristophe Pannecouque - Rega Institute for Medical ResearchAlexej Dick - Drexel UniversitySimon Cocklin - Drexel UniversityXinyong Liu - Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road,250012, Jinan, Shandong, PR China.Peng Zhan - Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road,250012, Jinan, Shandong, PR China.
- Publication Details
- European journal of medicinal chemistry, v 226, pp 113848-113848
- Publisher
- Elsevier
- Number of pages
- 18
- Grant note
- 2019JZZY021011 / Shandong Provincial Key research and development project 82173677; 81773574 / National Natural Science Foundation of China; National Natural Science Foundation of China (NSFC) R01AI150491 / NIH/NIAID; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) GXL20200015001 / Foreign cultural and educational experts Project ZR2020JQ31 / Science Foundation for Outstanding Young Scholars of Shandong Province Taishan Scholar Program at Shandong Province Qilu Young Scholars Program of Shandong University
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000703119000031
- Scopus ID
- 2-s2.0-85115984526
- Other Identifier
- 991019169651904721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal