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A Potent Human Immunodeficiency Virus Type 1 Protease Inhibitor, UIC-94003 (TMC-126), and Selection of a Novel (A28S) Mutation in the Protease Active Site

Kazuhisa Yoshimura,^1,2 Ryohei Kato,¹ Mark F. Kavlick,¹ Aline Nguyen,¹ Victor Maroun,¹ Kenji Maeda,² Khaja A. Hussain,³ Arun K. Ghosh,³ Sergei V. Gulnik,^4, John W. Erickson,^4, and Hiroaki Mitsuya^1,2,5*

Experimental Retrovirology Section, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,¹ Department of Internal Medicine II, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan,² Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607,³ Structural Biochemistry Program,⁴ HIV Clinical Interface Laboratory, Developmental Therapeutics Program, SAIC/National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702⁵

Received 6 February 2001/ Accepted 17 October 2001

We identified UIC-94003, a nonpeptidic human immunodeficiency virus (HIV) protease inhibitor (PI), containing 3(R),3a(S),6a(R)-bis-tetrahydrofuranyl urethane (bis-THF) and a sulfonamide isostere, which is extremely potent against a wide spectrum of HIV (50% inhibitory concentration, 0.0003 to 0.0005 µM). UIC-94003 was also potent against multi-PI-resistant HIV-1 strains isolated from patients who had no response to any existing antiviral regimens after having received a variety of antiviral agents (50% inhibitory concentration, 0.0005 to 0.0055 µM). Upon selection of HIV-1 in the presence of UIC-94003, mutants carrying a novel active-site mutation, A28S, in the presence of L10F, M46I, I50V, A71V, and N88D appeared. Modeling analysis revealed that the close contact of UIC-94003 with the main chains of the protease active-site amino acids (Asp29 and Asp30) differed from that of other PIs and may be important for its potency and wide-spectrum activity against a variety of drug-resistant HIV-1 variants. Thus, introduction of inhibitor interactions with the main chains of key amino acids and seeking a unique inhibitor-enzyme contact profile should provide a framework for developing novel PIs for treating patients harboring multi-PI-resistant HIV-1.

Present address: Tibotec, Inc., Rockville, MD 20850.

Present address: 5406 Jefferson Blvd., Frederick, MD 21703.

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