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

• Published in: Antimicrobial agents and chemotherapy Vol. 58; no. 7; pp. 3679 - 3688
• Main Authors: YEDIDI, Ravikiran S, GARIMELLA, Harisha, DAS, Debananda, WINGFIELD, Paul T, MAEDA, Kenji, GHOSH, Arun K, MITSUYA, Hiroaki, AOKI, Manabu, AOKI-OGATA, Hiromi, DESAI, Darshan V, CHANG, Simon B, DAVIS, David A, FYVIE, W. Sean, KAUFMAN, Joshua D, SMITH, David W
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.07.2014
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral Agents; Biological and medical sciences; Carbamates; Carbamates - pharmacology; Catalytic Domain; Catalytic Domain - drug effects; Crystallization; Darunavir; Drug Resistance, Multiple, Viral; Drug Resistance, Multiple, Viral - drug effects; Furans; Furans - pharmacology; HIV Protease; HIV Protease Inhibitors; HIV Protease Inhibitors - pharmacology; HIV-1; HIV-1 - drug effects; HIV-1 - enzymology; Human immunodeficiency virus 1; Humans; Hydrogen Bonding; Medical sciences; Molecular Conformation; Molecular Sequence Data; Pharmacology. Drug treatments; Protein Folding; Pyridines - pharmacology; Pyrones - pharmacology; Sulfonamides; Sulfonamides - pharmacology; X-Ray Diffraction; Immunopathology; Antiretroviral agent; Darunavir; HIV-1 virus; Active site; Retroviridae; Non peptide compound; AIDS; Immune deficiency; Lentivirus; Infection; Virus; Viral disease; Aminoacid; Multiple resistance; Antiviral; Human immunodeficiency virus; Mechanism of action; Protease inhibitor
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.00107-14

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.