Journal article
Design, Synthesis, and Mechanistic Study of 2-Pyridone-Bearing Phenylalanine Derivatives as Novel HIV Capsid Modulators
Molecules (Basel, Switzerland), v 27(21), p7640
07 Nov 2022
PMID: 36364467
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The AIDS pandemic is still of importance. HIV-1 and HIV-2 are the causative agents of this pandemic, and in the absence of a viable vaccine, drugs are continually required to provide quality of life for infected patients. The HIV capsid (CA) protein performs critical functions in the life cycle of HIV-1 and HIV-2, is broadly conserved across major strains and subtypes, and is underexploited. Therefore, it has become a therapeutic target of interest. Here, we report a novel series of 2-pyridone-bearing phenylalanine derivatives as HIV capsid modulators. Compound FTC-2 is the most potent anti-HIV-1 compound in the new series of compounds, with acceptable cytotoxicity in MT-4 cells (selectivity index HIV-1 > 49.57; HIV-2 > 17.08). However, compound TD-1a has the lowest EC50 in the anti-HIV-2 assays (EC50 = 4.86 ± 1.71 μM; CC50= 86.54 ± 29.24 μM). A water solubility test found that TD-1a showed a moderately increased water solubility compared with PF74, while the water solubility of FTC-2 was improved hundreds of times. Furthermore, we use molecular simulation studies to provide insight into the molecular contacts between the new compounds and HIV CA. We also computationally predict drug-like properties and metabolic stability for FTC-2 and TD-1a. Based on this analysis, TD-1a is predicted to have improved drug-like properties and metabolic stability over PF74. This study increases the repertoire of CA modulators and has important implications for developing anti-HIV agents with novel mechanisms, especially those that inhibit the often overlooked HIV-2.
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Details
- Title
- Design, Synthesis, and Mechanistic Study of 2-Pyridone-Bearing Phenylalanine Derivatives as Novel HIV Capsid Modulators
- Creators
- Xujie Zhang - Shandong UniversityLin Sun - Shandong UniversityShujing Xu - Shandong UniversityXiaoyu Shao - Shandong UniversityZiyi Li - Shandong UniversityDang Ding - Shandong UniversityXiangyi Jiang - Shandong UniversityShujie Zhao - Shandong UniversitySimon Cocklin - Specifica (United States)Erik De Clercq - Rega Institute for Medical ResearchChristophe Pannecouque - Rega Institute for Medical ResearchAlexej Dick - Drexel UniversityXinyong Liu - Shandong UniversityPeng Zhan - Shandong University
- Publication Details
- Molecules (Basel, Switzerland), v 27(21), p7640
- Publisher
- MDPI
- Grant note
- 82173677, 81773574, 82204196 / National Natural Science Foundation of China ZR2022QH015 / Shandong Provincial Natural Science Foundation 81420108027 / the Key Project of NSFC for International Cooperation R01AI150491 / NIH/NIAID grant 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:000885817500001
- Scopus ID
- 2-s2.0-85141831140
- Other Identifier
- 991021229904204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Multidisciplinary