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: Inge Dierynck, Herwig Van Marck, Marcia Van Ginderen, Tim H M Jonckers, Madhavi N L Nalam, Celia A Schiffer, Araz Raoof, Guenter Kraus, Gaston Picchio
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 55 Issue 12 Pg. 5723-31 (Dec 2011) ISSN: 1098-6596 [Electronic] United States
• PMID: 21896904 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• HIV Protease Inhibitors
• Sulfonamides
• HIV Protease
• p16 protease, Human immunodeficiency virus 1
• Darunavir

Topics

• Cell Line
• Crystallography, X-Ray
• Darunavir
• Drug Resistance, Viral (genetics)
• HIV Infections (virology)
• HIV Protease (chemistry, drug effects, genetics)
• HIV Protease Inhibitors (chemistry, pharmacology)
• HIV-1 (drug effects, enzymology, genetics, physiology)
• Humans
• Microbial Sensitivity Tests
• Molecular Sequence Data
• Mutation
• Sulfonamides (chemistry, pharmacology)