title: 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.
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 microM). 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 microM). 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.
authors.affiliation: Experimental Retrovirology Section, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Yoshimura
authors.forename: Ryohei
authors.initials: R
authors.lastname: Kato
authors.forename: Mark F
authors.initials: MF
authors.lastname: Kavlick
authors.forename: Aline
authors.initials: A
authors.lastname: Nguyen
authors.forename: Victor
authors.initials: V
authors.lastname: Maroun
authors.forename: Kenji
authors.initials: K
authors.lastname: Maeda
authors.forename: Khaja A
authors.initials: KA
authors.lastname: Hussain
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Gulnik
authors.forename: John W
authors.initials: JW
authors.lastname: Erickson
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D000409:Alanine / Q000235:genetics; D000595:Amino Acid Sequence; D020134:Catalytic Domain; D002460:Cell Line; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects / Q000201:enzymology* / Q000302:isolation & purification; D006801:Humans; D007753:Laboratories; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000235:genetics; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D014520:Urethane / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D017320:HIV Protease Inhibitors; D013449:Sulfonamides; C446340:UIC-94003; D014520:Urethane; D012694:Serine; D016333:HIV Protease; D000409:Alanine