5COP

X-ray crystal structure of wild type HIV-1 protease in complex with GRL-097

Summary for 5COP

• Entry DOI: 10.2210/pdb5cop/pdb
• Related: 4HLA 5COK 5CON 5COO
• Descriptor: HIV-1 protease, (3R,3aS,4S,7aS)-3-hydroxyhexahydro-4H-furo[2,3-b]pyran-4-yl [(2S,3R)-4-{[(4-aminophenyl)sulfonyl](2-methylpropyl)amino}-3-hydroxy-1-(4-methoxyphenyl)butan-2-yl]carbamate (3 entities in total)
• Functional Keywords: grl-097, hiv-1 protease, protease-inhibitor, darunavir, tp-thf, nonpeptidic, hydroxyl, o-methoxy., hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22213.26

Authors

Yedidi, R.S.,Hayashi, H.,Aoki, M.,Das, D.,Ghosh, A.K.,Mitsuya, H. (deposition date: 2015-07-20, release date: 2016-01-13, Last modification date: 2024-03-06)

Primary citation

Aoki, M.,Hayashi, H.,Yedidi, R.S.,Martyr, C.D.,Takamatsu, Y.,Aoki-Ogata, H.,Nakamura, T.,Nakata, H.,Das, D.,Yamagata, Y.,Ghosh, A.K.,Mitsuya, H.
C-5-Modified Tetrahydropyrano-Tetrahydofuran-Derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs, including Darunavir.
J.Virol., 90:2180-2194, 2015

PubMed Abstract: We identified three nonpeptidic HIV-1 protease inhibitors (PIs), GRL-015, -085, and -097, containing tetrahydropyrano-tetrahydrofuran (Tp-THF) with a C-5 hydroxyl. The three compounds were potent against a wild-type laboratory HIV-1 strain (HIV-1(WT)), with 50% effective concentrations (EC50s) of 3.0 to 49 nM, and exhibited minimal cytotoxicity, with 50% cytotoxic concentrations (CC50) for GRL-015, -085, and -097 of 80, >100, and >100 μM, respectively. All the three compounds potently inhibited the replication of highly PI-resistant HIV-1 variants selected with each of the currently available PIs and recombinant clinical HIV-1 isolates obtained from patients harboring multidrug-resistant HIV-1 variants (HIVMDR). Importantly, darunavir (DRV) was >1,000 times less active against a highly DRV-resistant HIV-1 variant (HIV-1DRV(R) P51); the three compounds remained active against HIV-1DRV(R) P51 with only a 6.8- to 68-fold reduction. Moreover, the emergence of HIV-1 variants resistant to the three compounds was considerably delayed compared to the case of DRV. In particular, HIV-1 variants resistant to GRL-085 and -097 did not emerge even when two different highly DRV-resistant HIV-1 variants were used as a starting population. In the structural analyses, Tp-THF of GRL-015, -085, and -097 showed strong hydrogen bond interactions with the backbone atoms of active-site amino acid residues (Asp29 and Asp30) of HIV-1 protease. A strong hydrogen bonding formation between the hydroxyl moiety of Tp-THF and a carbonyl oxygen atom of Gly48 was newly identified. The present findings indicate that the three compounds warrant further study as possible therapeutic agents for treating individuals harboring wild-type HIV and/or HIVMDR.

PubMed: 26581995
DOI: 10.1128/JVI.01829-15

Experimental method

X-RAY DIFFRACTION (2 Å)