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Antimicrobial Agents and Chemotherapy, October 2003, p. 3123-3129, Vol. 47, No. 10
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.10.3123-3129.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Novel bis-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI) UIC-94017 (TMC114) with Potent Activity against Multi-PI-Resistant Human Immunodeficiency Virus In Vitro

Yasuhiro Koh,1 Hirotomo Nakata,1 Kenji Maeda,1 Hiromi Ogata,1 Geoffrey Bilcer,2 Thippeswamy Devasamudram,2 John F. Kincaid,2 Peter Boross,3,4 Yuan-Fang Wang,3 Yunfeng Tie,5 Patra Volarath,5 Laquasha Gaddis,3 Robert W. Harrison,3,6 Irene T. Weber,3,5 Arun K. Ghosh,2 and Hiroaki Mitsuya1,7*

Department of Internal Medicine II, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan,1 Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607,2 Department of Biology,3 Department of Chemistry,5 Department of Computer Science, Georgia State University, Atlanta, Georgia,6 Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary,4 Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208927

Received 24 April 2003/ Returned for modification 18 June 2003/ Accepted 22 July 2003

We designed, synthesized, and identified UIC-94017 (TMC114), a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing a 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF) and a sulfonamide isostere which is extremely potent against laboratory HIV-1 strains and primary clinical isolates (50% inhibitory concentration [IC50], ~0.003 µM; IC90, ~0.009 µM) with minimal cytotoxicity (50% cytotoxic concentration for CD4+ MT-2 cells, 74 µM). UIC-94017 blocked the infectivity and replication of each of HIV-1NL4-3 variants exposed to and selected for resistance to saquinavir, indinavir, nelfinavir, or ritonavir at concentrations up to 5 µM (IC50s, 0.003 to 0.029 µM), although it was less active against HIV-1NL4-3 variants selected for resistance to amprenavir (IC50, 0.22 µM). UIC-94017 was also potent against multi-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. Structural analyses revealed that the close contact of UIC-94017 with the main chains of the protease active-site amino acids (Asp-29 and Asp-30) is important for its potency and wide spectrum of activity against multi-PI-resistant HIV-1 variants. Considering the favorable pharmacokinetics of UIC-94017 when administered with ritonavir, the present data warrant that UIC-94017 be further developed as a potential therapeutic agent for the treatment of primary and multi-PI-resistant HIV-1 infections.

* Corresponding author. Mailing address: Department of Internal Medicine II, 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.

Antimicrobial Agents and Chemotherapy, October 2003, p. 3123-3129, Vol. 47, No. 10
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.10.3123-3129.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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