5YOK

Structure of HIV-1 Protease in Complex with Inhibitor KNI-1657

Summary for 5YOK

• Entry DOI: 10.2210/pdb5yok/pdb
• Descriptor: HIV-1 PROTEASE, (4R)-N-[(2,6-dimethylphenyl)methyl]-3-[(2S,3S)-3-[[(2S)-2-[(7-methoxy-1-benzofuran-2-yl)carbonylamino]-2-[(3R)-oxolan-3 -yl]ethanoyl]amino]-2-oxidanyl-4-phenyl-butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, GLYCEROL, ... (4 entities in total)
• Functional Keywords: inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22684.84

Authors

Adachi, M.,Hidaka, K.,Kuroki, R.,Kiso, Y. (deposition date: 2017-10-29, release date: 2018-07-18, Last modification date: 2024-03-27)

Primary citation

Hidaka, K.,Kimura, T.,Sankaranarayanan, R.,Wang, J.,McDaniel, K.F.,Kempf, D.J.,Kameoka, M.,Adachi, M.,Kuroki, R.,Nguyen, J.T.,Hayashi, Y.,Kiso, Y.
Identification of Highly Potent Human Immunodeficiency Virus Type-1 Protease Inhibitors against Lopinavir and Darunavir Resistant Viruses from Allophenylnorstatine-Based Peptidomimetics with P2 Tetrahydrofuranylglycine.
J. Med. Chem., 61:5138-5153, 2018

PubMed Abstract: The emergence of drug-resistant HIV from a widespread antiviral chemotherapy targeting HIV protease in the past decades is unavoidable and provides a challenge to develop alternative inhibitors. We synthesized a series of allophenylnorstatine-based peptidomimetics with various P, P, and Ṕ moieties. The derivatives with P tetrahydrofuranylglycine (Thfg) were found to be potent against wild type HIV-1 protease and the virus, leading to a highly potent compound 21f (KNI-1657) against lopinavir/ritonavir- or darunavir-resistant strains. Co-crystal structures of 21f and the wild-type protease revealed numerous key hydrogen bonding interactions with Thfg. These results suggest that the strategy to design allophenylnorstatine-based peptidomimetics combined with Thfg residue would be promising for generating candidates to overcome multidrug resistance.

PubMed: 29852069
DOI: 10.1021/acs.jmedchem.7b01709

Experimental method

X-RAY DIFFRACTION (0.85 Å)