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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

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-1_NL4-3 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-1_NL4-3 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.

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