5WLO

a novel 13-ring macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands

Summary for 5WLO

• Entry DOI: 10.2210/pdb5wlo/pdb
• Related: 3I6O
• Descriptor: Protease, SODIUM ION, CHLORIDE ION, ... (7 entities in total)
• Functional Keywords: hiv protease, macrocyclic inhibitors, p1'- p2' ligands, drug resistance, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22463.50

Authors

Wang, Y.-F.,Agniswamy, J.,Weber, I.T. (deposition date: 2017-07-27, release date: 2017-10-11, Last modification date: 2023-10-04)

Primary citation

Ghosh, A.K.,Sean Fyvie, W.,Brindisi, M.,Steffey, M.,Agniswamy, J.,Wang, Y.F.,Aoki, M.,Amano, M.,Weber, I.T.,Mitsuya, H.
Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands.
Bioorg. Med. Chem. Lett., 27:4925-4931, 2017

PubMed Abstract: Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1'-P2' tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (K=13.2nM, IC=22nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. These compounds showed excellent HIV-1 protease inhibitory (K=62pM and 14pM, respectively) and antiviral activity (IC=5.3nM and 2.0nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.

PubMed: 28958624
DOI: 10.1016/j.bmcl.2017.09.003

Experimental method

X-RAY DIFFRACTION (1.27 Å)