6U7P

HIV-1 wild type protease with GRL-03119A, with phenyl-boronic-acid as P2'-ligand and with a hexahydro-4H-furo-pyran as the P2-ligand

Summary for 6U7P

• Entry DOI: 10.2210/pdb6u7p/pdb
• Related: 2IEN 4I8W 4I8Z 6C8X 6U7O
• Descriptor: Protease, {4-[{(2R,3S)-3-[({[(3aS,4S,7aR)-hexahydro-4H-furo[2,3-b]pyran-4-yl]oxy}carbonyl)amino]-2-hydroxy-4-phenylbutyl}(2-methylpropyl)sulfamoyl]phenyl}boronic acid, SODIUM ION, ... (7 entities in total)
• Functional Keywords: aspartic acid protease, hiv-1 protease inhibitor of grl-03119a, boronic acid, viral protein
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22410.22

Authors

Wang, Y.-F.,Kneller, D.W.,Weber, I.T. (deposition date: 2019-09-03, release date: 2019-10-09, Last modification date: 2023-10-11)

Primary citation

Ghosh, A.K.,Xia, Z.,Kovela, S.,Robinson, W.L.,Johnson, M.E.,Kneller, D.W.,Wang, Y.F.,Aoki, M.,Takamatsu, Y.,Weber, I.T.,Mitsuya, H.
Potent HIV-1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein-Ligand X-ray Structural Studies.
Chemmedchem, 14:1863-1872, 2019

PubMed Abstract: We report the synthesis and biological evaluation of phenylcarboxylic acid and phenylboronic acid containing HIV-1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT-2 cell lines. Inhibitors bearing bis-THF ligand as P2 ligand and phenylcarboxylic acids and carboxamide as the P2' ligands, showed very potent HIV-1 protease inhibitory activity. However, carboxylic acid containing inhibitors showed very poor antiviral activity relative to carboxamide-derived inhibitors which showed good antiviral IC value. Boronic acid derived inhibitor with bis-THF as the P2 ligand showed very potent enzyme inhibitory activity, but it showed lower antiviral activity than darunavir in the same assay. Boronic acid containing inhibitor with a P2-Crn-THF ligand also showed potent enzyme K but significantly decreased antiviral activity. We have evaluated antiviral activity against a panel of highly drug-resistant HIV-1 variants. One of the inhibitors maintained good antiviral activity against HIV and HIV viruses. We have determined high resolution X-ray structures of two synthetic inhibitors bound to HIV-1 protease and obtained molecular insight into the ligand-binding site interactions.

PubMed: 31549492
DOI: 10.1002/cmdc.201900508

Experimental method

X-RAY DIFFRACTION (1.13 Å)