期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 58, 期 7, 页码 3679-3688出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.00107-14
关键词
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资金
- Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health
- Ministry of Health, Welfare, and Labor of Japan
- Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Re-emerging Infectious Diseases of Monbukagakusho (Kumamoto University) of Monbukagakusho [78]
- National Institutes of Health [GM53386]
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE AC02 06CH11357, W 31 109 Eng 38]
- Michigan Economic Development Corporation
- Michigan Technology Tri-Corridor [085P1000817]
- Grants-in-Aid for Scientific Research [26293239] Funding Source: KAKEN
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 [EC(50)s], 0.029 and 0.002 mu M, respectively) against a multidrug-resistant clinical isolate of HIV-1 (HIVA02) compared to ritonavir (RTV; EC50, > 1.0 mu M) and tipranavir (TPV; EC50, 0.364 mu M). Additionally, GRL008 showed potent antiviral activity against an HIV-1 variant selected in the presence of DRV over 20 passages (HIVDRVP20R), with a 2.6-fold increase in its EC50 (0.097 mu M) compared to its corresponding EC50 (0.038 mu M) against wild-type HIV-1(NL4-3) (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 mu M). 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 HIVDRVP20R.
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