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

• DOI: 10.1128/jvi.76.3.1349-1358.2002
• Publication Date: 2010-10-27T14:32:49Z
• Authors: Kazuhisa Yoshimura; Ryohei Kato; Mark F. Kavlick; Aline Nguyen; Victor Maroun; Kenji Maeda; Khaja A. Hussain; Arun K. Ghosh; Sergei V. Gulnik; John W. Erickson; Hiroaki Mitsuya
• Keywords: Models, Molecular; 0301 basic medicine; Sulfonamides; Alanine; Molecular Structure; Sequence Homology, Amino Acid; Molecular Sequence Data; HIV Protease Inhibitors; Urethane; Cell Line; Protein Structure, Tertiary; 3. Good health; 03 medical and health sciences; HIV Protease; Catalytic Domain; HIV-1; Mutagenesis, Site-Directed; Serine; Humans; Amino Acid Sequence; Laboratories

ABSTRACT

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.