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Journal of Virology, February 2002, p. 1349-1358, Vol. 76, No. 3
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.3.1349-1358.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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,{dagger} John W. Erickson,4,{ddagger} and Hiroaki Mitsuya1,2,5*

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.

* Corresponding author. Mailing address: Experimental Retrovirology Section, Medicine Branch, National Cancer Institute, Bldg. 10, Rm. 5A11, Bethesda, MD 20892. Phone: (301) 496-9238. Fax: (301) 402-0709. E-mail: hmitsuya{at}helix.nih.gov.

{dagger} Present address: Tibotec, Inc., Rockville, MD 20850.

{ddagger} Present address: 5406 Jefferson Blvd., Frederick, MD 21703.

Journal of Virology, February 2002, p. 1349-1358, Vol. 76, No. 3
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.3.1349-1358.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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