Journal article
Discovery of low-molecular-weight phenylalanine derivatives as novel HIV capsid modulators with improved antiretroviral activity and metabolic stability
Journal of medical virology, v 96(4), pe29594
Apr 2024
PMID: 38576317
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The HIV capsid (CA) protein is a promising target for anti-AIDS treatment due to its critical involvement in viral replication. Herein, we utilized the well-documented CA inhibitor PF74 as our lead compound and designed a series of low-molecular-weight phenylalanine derivatives. Among them, compound 7t exhibited remarkable antiviral activity with a high selection index (EC
= 0.040 µM, SI = 2815), surpassing that of PF74 (EC
= 0.50 µM, SI = 258). Furthermore, when evaluated against the HIV-2 strain, 7t (EC
= 0.13 µM) demonstrated approximately 14-fold higher potency than that of PF74 (EC
= 1.76 µM). Insights obtained from surface plasmon resonance (SPR) revealed that 7t exhibited stronger target affinity to the CA hexamer and monomer in comparison to PF74. The potential interactions between 7t and the HIV-1 CA were further elucidated using molecular docking and molecular dynamics simulations, providing a plausible explanation for the enhanced target affinity with 7t over PF74. Moreover, the metabolic stability assay demonstrated that 7t (T
= 77.0 min) significantly outperforms PF74 (T
= 0.7 min) in human liver microsome, exhibiting an improvement factor of 110-fold. In conclusion, 7t emerges as a promising drug candidate warranting further investigation.
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Details
- Title
- Discovery of low-molecular-weight phenylalanine derivatives as novel HIV capsid modulators with improved antiretroviral activity and metabolic stability
- Creators
- Xiangyi Jiang - University of JinanZhen Gao - University of JinanPrem Prakash Sharma - HeteroChem InnoTech, Hansraj College Campus (University of Delhi), Delhi, IndiaSumit Kumar - HeteroChem InnoTech, Hansraj College Campus (University of Delhi), Delhi, IndiaBrijesh Rathi - University of DelhiXiangkai Ji - University of JinanJiaojiao Dai - University of JinanMinghui Xie - University of JinanGuanyu Dong - University of JinanShujing Xu - University of JinanErik De Clercq - Rega Institute for Medical ResearchChristophe Pannecouque - Rega Institute for Medical ResearchAlexej Dick - Drexel UniversityPeng Zhan - China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, Jinan, Shandong, People's Republic of ChinaXinyong Liu - China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, Jinan, Shandong, People's Republic of China
- Publication Details
- Journal of medical virology, v 96(4), pe29594
- Publisher
- Wiley
- Grant note
- National Natural Science Foundation of China (NSFC No. 82173677), Key Research and Development Program, Ministry of Science and Technology of the People's Republic of China (Grant No. 2023YFC2606500; 2023YFE0206500), Science Foundation for Outstanding Young Scholars of Shandong Province (ZR2020JQ31), Shandong Laboratory Program (SYS202205), and NIH/NIAID grant R01AI150491 (Loll, PI, Salvino, Co-I) 2023YFC2606500 / Key Research and Development Program, Ministry of Science and Technology of the People's Republic of China R01AI150491 / National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) 82173677 / National Natural Science Foundation of China SYS202205 / Shandong Laboratory Program 2023YFE0206500 / Key Research and Development Program, Ministry of Science and Technology of the People's Republic of China ZR2020JQ31 / Science Foundation for Outstanding Young Scholars of Shandong Province
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:001262910300030
- Scopus ID
- 2-s2.0-85190079033
- Other Identifier
- 991021866482904721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Virology