4NJS

Crystal structure of multidrug-resistant clinical isolate A02 HIV-1 protease in complex with non-peptidic inhibitor, GRL008

Summary for 4NJS

• Entry DOI: 10.2210/pdb4njs/pdb
• Related: 4HLA 4I8W 4I8Z 4NJT 4NJU 4NJV
• Descriptor: Protease, (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-4-{[(4-carbamoylphenyl)sulfonyl](2-methylpropyl)amino}-3-hydroxy-1-phenylbutan-2-yl]carbamate (3 entities in total)
• Functional Keywords: multidrug-resistance, hiv-1 protease, non-peptidic inhibitor, protease inhibitor, darunavir analog, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 4
• Total formula weight: 44606.34

Authors

Yedidi, R.S.,Garimella, H.,Kaufman, J.D.,Das, D.,Wingfield, P.T.,Ghosh, A.K.,Mitsuya, H. (deposition date: 2013-11-11, release date: 2014-04-02, Last modification date: 2024-02-28)

Primary citation

Yedidi, R.S.,Garimella, H.,Aoki, M.,Aoki-Ogata, H.,Desai, D.V.,Chang, S.B.,Davis, D.A.,Fyvie, W.S.,Kaufman, J.D.,Smith, D.W.,Das, D.,Wingfield, P.T.,Maeda, K.,Ghosh, A.K.,Mitsuya, H.
A Conserved Hydrogen-Bonding Network of P2 bis-Tetrahydrofuran-Containing HIV-1 Protease Inhibitors (PIs) with a Protease Active-Site Amino Acid Backbone Aids in Their Activity against PI-Resistant HIV.
Antimicrob.Agents Chemother., 58:3679-3688, 2014

PubMed Abstract: In the present study, GRL008, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI), and darunavir (DRV), both of which contain a P2-bis-tetrahydrofuranyl urethane (bis-THF) moiety, were found to exert potent antiviral activity (50% effective concentrations [EC50s], 0.029 and 0.002 μM, respectively) against a multidrug-resistant clinical isolate of HIV-1 (HIVA02) compared to ritonavir (RTV; EC50, >1.0 μM) and tipranavir (TPV; EC50, 0.364 μM). Additionally, GRL008 showed potent antiviral activity against an HIV-1 variant selected in the presence of DRV over 20 passages (HIVDRV(R)P20), with a 2.6-fold increase in its EC50 (0.097 μM) compared to its corresponding EC50 (0.038 μM) against wild-type HIV-1NL4-3 (HIVWT). Based on X-ray crystallographic analysis, both GRL008 and DRV showed strong hydrogen bonds (H-bonds) with the backbone-amide nitrogen/carbonyl oxygen atoms of conserved active-site amino acids G27, D29, D30, and D30' of HIVA02 protease (PRA02) and wild-type PR in their corresponding crystal structures, while TPV lacked H-bonds with G27 and D30' due to an absence of polar groups. The P2' thiazolyl moiety of RTV showed two conformations in the crystal structure of the PRA02-RTV complex, one of which showed loss of contacts in the S2' binding pocket of PRA02, supporting RTV's compromised antiviral activity (EC50, >1 μM). Thus, the conserved H-bonding network of P2-bis-THF-containing GRL008 with the backbone of G27, D29, D30, and D30' most likely contributes to its persistently greater antiviral activity against HIVWT, HIVA02, and HIVDRV(R)P20.

PubMed: 24752271
DOI: 10.1128/AAC.00107-14

Experimental method

X-RAY DIFFRACTION (1.8 Å)