title: TMC310911, a novel human immunodeficiency virus type 1 protease inhibitor, shows in vitro an improved resistance profile and higher genetic barrier to resistance compared with current protease inhibitors.
abstract: TMC310911 is a novel human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) structurally closely related to darunavir (DRV) but with improved virological characteristics. TMC310911 has potent activity against wild-type (WT) HIV-1 (median 50% effective concentration [EC(50)], 14 nM) and a wide spectrum of recombinant HIV-1 clinical isolates, including multiple-PI-resistant strains with decreased susceptibility to currently approved PIs (fold change [FC] in EC(50), >10). For a panel of 2,011 recombinant clinical isolates with decreased susceptibility to at least one of the currently approved PIs, the FC in TMC310911 EC(50) was ≤ 4 for 82% of isolates and ≤ 10 for 96% of isolates. The FC in TMC310911 EC(50) was ≤ 4 and ≤ 10 for 72% and 94% of isolates with decreased susceptibility to DRV, respectively. In vitro resistance selection (IVRS) experiments with WT virus and TMC310911 selected for mutations R41G or R41E, but selection of resistant virus required a longer time than IVRS performed with WT virus and DRV. IVRS performed with r13025, a multiple-PI-resistant recombinant clinical isolate, and TMC310911 selected for mutations L10F, I47V, and L90M (FC in TMC310911 EC(50) = 16). IVRS performed with r13025 in the presence of DRV required less time and resulted in more PI resistance-associated mutations (V32I, I50V, G73S, L76V, and V82I; FC in DRV EC(50) = 258). The activity against a comprehensive panel of PI-resistant mutants and the limited in vitro selection of resistant viruses under drug pressure suggest that TMC310911 represents a potential drug candidate for the management of HIV-1 infection for a broad range of patients, including those with multiple PI resistance.
authors: Tibotec BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium. idierinc@its.jnj.com
authors: Inge
authors: I
authors: Dierynck
authors: Herwig
authors: H
authors: Van Marck
authors: Marcia
authors: M
authors: Van Ginderen
authors: Tim H M
authors: TH
authors: Jonckers
authors: Madhavi N L
authors: MN
authors: Nalam
authors: Celia A
authors: CA
authors: Schiffer
authors: Araz
authors: A
authors: Raoof
authors: Guenter
authors: G
authors: Kraus
authors: Gaston
authors: G
authors: Picchio
mesh_terms: D002460:Cell Line; D018360:Crystallography, X-Ray; D000069454:Darunavir; D024882:Drug Resistance, Viral / Q000235:genetics*; D015658:HIV Infections / Q000821:virology*; D016333:HIV Protease / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009154:Mutation; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology
chemical_list: D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D000069454:Darunavir