Journal
MOLECULES
Volume 27, Issue 21, Pages -Publisher
MDPI
DOI: 10.3390/molecules27217640
Keywords
HIV; capsid; phenylalanine derivatives; protein-protein interaction
Funding
- National Natural Science Foundation of China (NSFC) [82173677, 81773574, 82204196]
- Key Project of NSFC for International Cooperation [81420108027]
- Science Foundation for Outstanding Young Scholars of Shandong Province [ZR2020JQ31]
- Qilu Young Scholars Program of Shandong University
- Taishan Scholar Program at Shandong Province
- Shandong Provincial Natural Science Foundation [ZR2022QH015]
- NIH/NIAID [R01AI150491]
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The AIDS pandemic remains significant, and the HIV capsid protein has become an interesting therapeutic target. This study introduces a novel series of 2-pyridone-bearing phenylalanine derivatives as HIV capsid modulators, with compounds FTC-2 and TD-1a showing potential anti-HIV activity.
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 mu M; CC50 = 86.54 +/- 29.24 mu M). 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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