Structural highlights
Publication Abstract from PubMed
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 antiviral 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 multi PI-resistant strains with decreased susceptibility to currently approved PIs (fold change in EC(50) [FC]>10). On a panel of 2011 recombinant clinical isolates with decreased susceptibility to at least one of the currently approved PIs, the FC in EC(50) for TMC310911 was </=4 for 82% of isolates, and </=10 for 96% of isolates. TMC310911 had a FC</=4 and a FC</=10 for 72% and 94% of isolates with a 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 with WT virus and DRV. IVRS with a multi PI-resistant recombinant clinical isolate r13025 with TMC310911 selected for mutations L10F, I47V, and L90M (TMC310911 FC=16). IVRS with r13025 in the presence of DRV required less time and resulted in more PI resistance-associated mutations (V32I, I50V, G73S, L76V, and V82I, DRV FC=258). The antiviral 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.
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 I, Van Marck H, Van Ginderen M, Jonckers TH, Nalam MN, Schiffer CA, Raoof A, Kraus G, Picchio G Antimicrob Agents Chemother. 2011 Sep 6. PMID:21896904[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Dierynck I, Van Marck H, Van Ginderen M, Jonckers TH, Nalam MN, Schiffer CA, Raoof A, Kraus G, Picchio G. 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. Antimicrob Agents Chemother. 2011 Sep 6. PMID:21896904 doi:10.1128/AAC.00748-11
