4M8Y

GS-8374, a Novel Phosphonate-Containing Inhibitor of HIV-1 Protease, Effectively Inhibits HIV PR Mutants with Amino Acid Insertions

Summary for 4M8Y

• Entry DOI: 10.2210/pdb4m8y/pdb
• Related: 2RKF 2RKG 4M8X
• Descriptor: Protease, DIETHYL ({4-[(2S,3R)-2-({[(3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YLOXY]CARBONYL}AMINO)-3-HYDROXY-4-{ISOBUTYL[(4-METHOXYPHENYL)SULFONYL]AMINO}BUTYL]PHENOXY}METHYL)PHOSPHONATE (3 entities in total)
• Functional Keywords: hiv-1 protease, aspartic protease, amino acid insertion, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 23283.12

Authors

Grantz saskova, K.,Brynda, J.,Rezacova, P.,Kozisek, M.,Konvalinka, J. (deposition date: 2013-08-14, release date: 2014-05-07, Last modification date: 2023-09-20)

Primary citation

Grantz Saskova, K.,Kozisek, M.,Stray, K.,de Jong, D.,Rezaova, P.,Brynda, J.,van Maarseveen, N.M.,Nijhuis, M.,Cihlar, T.,Konvalinka, J.
GS-8374, a prototype phosphonate-containing inhibitor of HIV-1 protease, effectively inhibits protease mutants with amino acid insertions.
J.Virol., 88:3586-3590, 2014

PubMed Abstract: Insertions in the protease (PR) region of human immunodeficiency virus (HIV) represent an interesting mechanism of antiviral resistance against HIV PR inhibitors (PIs). Here, we demonstrate the improved ability of a phosphonate-containing experimental HIV PI, GS-8374, relative to that of other PIs, to effectively inhibit patient-derived recombinant HIV strains bearing PR insertions and numerous other mutations. We correlate enzyme inhibition with the catalytic activities of corresponding recombinant PRs in vitro and provide a biochemical and structural analysis of the PR-inhibitor complex.

PubMed: 24371077
DOI: 10.1128/JVI.02688-13

Experimental method

X-RAY DIFFRACTION (2.22 Å)