This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Amano, M.
Right arrow Articles by Mitsuya, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Amano, M.
Right arrow Articles by Mitsuya, H.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, June 2007, p. 2143-2155, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01413-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Novel Bis-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI), GRL-98065, Is Potent against Multiple-PI-Resistant Human Immunodeficiency Virus In Vitro{triangledown}

Masayuki Amano,1,2 Yasuhiro Koh,1,2 Debananda Das,3 Jianfeng Li,4 Sofiya Leschenko,4 Yuan-Fang Wang,5 Peter I. Boross,5,6 Irene T. Weber,5 Arun K. Ghosh,4 and Hiroaki Mitsuya1,2,3*

Department of Infectious Diseases,1 Department of Hematology, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan,2 Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,3 Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907,4 Department of Biology, Georgia State University, Atlanta, Georgia 30303,5 Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary6

Received 13 November 2006/ Returned for modification 5 January 2007/ Accepted 12 March 2007

We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC50], 0.0002 to 0.0005 µM) with minimal cytotoxicity (50% cytotoxicity, 35.7 µM in CD4+ MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1NL4-3 variants exposed to and selected by up to a 5 µM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 µM concentration of lopinavir or atazanavir (EC50, 0.0015 to 0.0075 µM), although it was less active against HIV-1NL4-3 selected by amprenavir (EC50, 0.032 µM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.

* Corresponding author. Mailing address: Departments of Infectious Diseases and Hematology, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan. Phone: (81) 96-373-5156. Fax: (81) 96-363-5265. E-mail: hm21q{at}nih.gov

{triangledown} Published ahead of print on 19 March 2007.

Antimicrobial Agents and Chemotherapy, June 2007, p. 2143-2155, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01413-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Aoki, M., Venzon, D. J., Koh, Y., Aoki-Ogata, H., Miyakawa, T., Yoshimura, K., Maeda, K., Mitsuya, H. (2009). Non-Cleavage Site Gag Mutations in Amprenavir-Resistant Human Immunodeficiency Virus Type 1 (HIV-1) Predispose HIV-1 to Rapid Acquisition of Amprenavir Resistance but Delay Development of Resistance to Other Protease Inhibitors. J. Virol. 83: 3059-3068 [Abstract] [Full Text]  
  • Koh, Y., Das, D., Leschenko, S., Nakata, H., Ogata-Aoki, H., Amano, M., Nakayama, M., Ghosh, A. K., Mitsuya, H. (2009). GRL-02031, a Novel Nonpeptidic Protease Inhibitor (PI) Containing a Stereochemically Defined Fused Cyclopentanyltetrahydrofuran Potent against Multi-PI-Resistant Human Immunodeficiency Virus Type 1 In Vitro. Antimicrob. Agents Chemother. 53: 997-1006 [Abstract] [Full Text]  
  • Koh, Y., Matsumi, S., Das, D., Amano, M., Davis, D. A., Li, J., Leschenko, S., Baldridge, A., Shioda, T., Yarchoan, R., Ghosh, A. K., Mitsuya, H. (2007). Potent Inhibition of HIV-1 Replication by Novel Non-peptidyl Small Molecule Inhibitors of Protease Dimerization. J. Biol. Chem. 282: 28709-28720 [Abstract] [Full Text]  
  • Nakata, H., Amano, M., Koh, Y., Kodama, E., Yang, G., Bailey, C. M., Kohgo, S., Hayakawa, H., Matsuoka, M., Anderson, K. S., Cheng, Y.-C., Mitsuya, H. (2007). Activity against Human Immunodeficiency Virus Type 1, Intracellular Metabolism, and Effects on Human DNA Polymerases of 4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine. Antimicrob. Agents Chemother. 51: 2701-2708 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»