期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 57, 期 5, 页码 2036-2046出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.02189-12
关键词
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资金
- Grant for Global Education and Research Center Aiming at the Control of AIDS (Global Center of Excellence, supported by Monbu-Kagakusho)
- Ministry of Health, Welfare, and Labor of Japan
- Intramural Research Program of the Center for Cancer Research
- Monbu-Kagakusho
- National Cancer Institute, National Institutes of Health
- National Institutes of Health [GM53386]
- Grants-in-Aid for Scientific Research [23791140, 24659484, 23390265] Funding Source: KAKEN
We report that GRL-0519, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing tris-tetrahydrofuranylurethane (tris-THF) and a sulfonamide isostere, is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC50], 0.0005 to 0.0007 mu M) with minimal cytotoxicity (50% cytotoxic concentration [CC50], 44.6 mu M). GRL-0519 blocked the infectivity and replication of HIV-1(NL4-3) variants selected by up to a 5 mu M concentration of ritonavir, lopinavir, or atazanavir (EC50, 0.0028 to 0.0033 mu M). GRL-0519 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who no longer responded to existing antiviral regimens after long-term antiretroviral therapy, highly darunavir (DRV)-resistant variants, and HIV-2(ROD). The development of resistance against GRL-0519 was substantially delayed compared to other PIs, including amprenavir (APV) and DRV. The effects of nonspecific binding of human serum proteins on GRL-0519's antiviral activity were insignificant. Our analysis of the crystal structures of GRL-0519 (3OK9) and DRV (2IEN) with protease suggested that the tris-THF moiety, compared to the bis-THF moiety present in DRV, has greater water-mediated polar interactions with key active-site residues of protease and that the tris-THF moiety and paramethoxy group effectively fill the S2 and S2' binding pockets, respectively, of the protease. The present data demonstrate that GRL-0519 has highly favorable features as a potential therapeutic agent for treating patients infected with wild-type and/or multi-PI-resistant variants and that the tris-THF moiety is critical for strong binding of GRL-0519 to the HIV protease substrate binding site and appears to be responsible for its favorable antiretroviral characteristics.
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