Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
A series of novel potent HIV-1 protease inhibitors featuring diverse hydroxyaromatic acetanilide derivatives as P2 ligands and 4-substituted phenyl sulfonamides as P2' ligands were designed, synthesized, and biologically evaluated. The majority of the target compounds demonstrated potent enzyme inhibitory activity with IC values below100 nM. Notably, compound 18h, incorporating a 2-(4-hydroxypyrimidin-5-yl) acetamide P2 ligand and a 4-methoxybenzenesulfonamide as the P2' ligand, exhibited exceptional potency with an enzyme IC of 0.46 nM and antiviral EC of 0.26 μM against HIV-1 strain. In addition, 18h displayed activity with EC value of 0.25 μM against the subtype C HIV-1 Indie strain. The extensive hydrogen-bonding interactions with the protease active site revealed in the molecular docking analysis of 18h-bound HIV-1 protease provided valuable structural insights for the rational design of next-generation HIV-1 protease inhibitors.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmc.2025.118338 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
HIV-1 particle assembly depends critically on multiple proteolytic cleavages of viral polyproteins by the viral protease, PR. PR is translated as part of the Gag-Pro-Pol polyprotein, which undergoes autoproteolysis to liberate active, dimeric PR during virus particle maturation. Gag-Pro-Pol is produced via an infrequent -1 frameshifting event in ribosomes translating full length genomic RNA as Gag mRNA.
View Article and Find Full Text PDFMechanistic basis for a novel dual-function Gag-Pol dimerizer potentiating CARD8 inflammasome activation and clearance of HIV-infected cells.
NPJ Drug Discov
September 2025
Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT USA.
A strategy to functionally cure AIDS by eliminating latent HIV-1 reservoirs involves non-nucleoside reverse transcriptase inhibitors (NNRTIs) that promote pyroptosis of HIV-1 infected cells. These NNRTIs stimulate dimerization of the Gag-Pol polyprotein, resulting in premature HIV-1 protease (PR) dimerization and cleavage of intracellular CARD8. A unique cell-based high-throughput screen was developed to identify potent compounds activating the CARD8 inflammasome through Gag-Pol dimerization.
View Article and Find Full Text PDFESMDynamic: Fast and Accurate Prediction of Protein Dynamic Contact Maps from Single Sequences.
bioRxiv
August 2025
Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
Understanding conformational dynamics is essential for elucidating protein function, yet most deep learning models in structural biology predict only static structures. Here, we introduce ESMDynamic, a deep learning model that predicts dynamic residue-residue contact probability maps directly from protein sequence. Built on the ESMFold architecture, ESMDynamic is trained on contact fluctuations from experimental structure ensembles and molecular dynamics (MD) simulations, enabling it to capture diverse modes of structural variability without requiring multiple sequence alignments.
View Article and Find Full Text PDFSubtype-Specific HIV-1 Protease and the Role of Hinge and Flap Dynamics in Drug Resistance: A Subtype C Narrative.
Viruses
July 2025
Protein Structure-Function Research Laboratory, University of the Witwatersrand, Johannesburg 2000, South Africa.
The HIV-1 aspartic protease is an effective target for the treatment of HIV/AIDS. Current therapy utilizes a selection of nine protease inhibitors (PIs) in combination with other classes of antiretroviral drugs. Although PIs were originally developed based on the knowledge of the HIV-1 subtype B protease, the existence of other HIV-1 subtypes and the effects of drug resistance on currently available PIs have become a major challenge in the treatment of HIV/AIDS.
View Article and Find Full Text PDFRational design, synthesis, and evaluating primary biological activities of novel HIV-1 protease inhibitors containing heteraryl acetamides as the P2 ligands.
Bioorg Med Chem
November 2025
Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China. Electronic address:
A series of novel potent HIV-1 protease inhibitors featuring diverse hydroxyaromatic acetanilide derivatives as P2 ligands and 4-substituted phenyl sulfonamides as P2' ligands were designed, synthesized, and biologically evaluated. The majority of the target compounds demonstrated potent enzyme inhibitory activity with IC values below100 nM. Notably, compound 18h, incorporating a 2-(4-hydroxypyrimidin-5-yl) acetamide P2 ligand and a 4-methoxybenzenesulfonamide as the P2' ligand, exhibited exceptional potency with an enzyme IC of 0.
View Article and Find Full Text PDF