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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.
Dierynck, Inge; Van Marck, Herwig; Van Ginderen, Marcia; Jonckers, Tim H M; Nalam, Madhavi N L; Schiffer, Celia A; Raoof, Araz; Kraus, Guenter; Picchio, Gaston.
Afiliação
  • Dierynck I; Tibotec BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium. idierinc@its.jnj.com
Antimicrob Agents Chemother ; 55(12): 5723-31, 2011 Dec.
Article em En | MEDLINE | ID: mdl-21896904
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Infecções por HIV / Protease de HIV / HIV-1 / Inibidores da Protease de HIV / Farmacorresistência Viral Idioma: En Ano de publicação: 2011 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Infecções por HIV / Protease de HIV / HIV-1 / Inibidores da Protease de HIV / Farmacorresistência Viral Idioma: En Ano de publicação: 2011 Tipo de documento: Article