Disease relevance of TMC 114

• Darunabir, formerly TMC114, is a new protease inhibitor (PI) under clinical development designed to be active against HIV strains resistant to currently available PI [1].
• HIV-1 RNA < 400 copies/ml at any time during treatment was achieved by 40% in the TMC114/RTV groups and 8% in the control group [2].

High impact information on TMC 114

• Ultra-high Resolution Crystal Structure of HIV-1 Protease Mutant Reveals Two Binding Sites for Clinical Inhibitor TMC114 [3].
• Other small differences were observed in the interactions of the mutants with UIC-94017 as compared to PR [4].
• Our X-ray data (resolution ranging from 2.2 to 1.2 A) reveal strong interactions between the bis-tetrahydrofuranyl urethane moiety of TMC114 and main-chain atoms of D29 and D30 [5].
• Antiretroviral salvage therapy takes advantage of the development or availability of new drugs, either from existing (tipranavir, TMC 114 as new PIs) or new classes (T20 as a fusion inhibitor), that remain active on many triple-class drug resistant viruses [6].
• Three out of the four existing antiretroviral classes (nucleosides, non-nucleosides, protease inhibitors) with agents in clinical trials will be discussed such as nucleoside reverse transcriptase inhibitors (D-d4FC, SPD754), non-nucleoside reverse transcriptase inhibitors (capravirine, TMC125) and protease inhibitors (tipranavir, TMC114) [7].

Biological context of TMC 114

• These structures show TMC114 bound at two distinct sites, one in the active-site cavity and the second on the surface of one of the flexible flaps in the PR dimer [3].
• The Effect of Different Meal Types on the Pharmacokinetics of Darunavir (TMC114)/Ritonavir in HIV-Negative Healthy Volunteers [8].
• This open-label, randomized, crossover study investigated the bioavailability, short-term safety, and tolerability of darunavir (TMC114) coadministered with low-dose ritonavir under fasted conditions and after different meal types in HIV-negative healthy volunteers [8].
• SCOPE: This review describes the challenges posed by HIV drug resistance and the novel approach taken in the design and selection of TMC114 [9].

Associations of TMC 114 with other chemical compounds

• Patients harbouring viruses with amprenavir-specific resistance profiles, such as I50V or V32I + I47V, failed on a darunavir/ritonavir-containing regimen [10].

Analytical, diagnostic and therapeutic context of TMC 114

• Median change at day 14 was -1.38 and +0.02 log10 copies/ml for all TMC114/RTV groups and the control group, respectively [2].
• However, when the selected mutations were introduced into a laboratory strain by site-directed mutagenesis, they had no effect on susceptibility to TMC114 or other PIs [11].
• Articles were identified by searching MEDLINE in September 2005 (search limits: 1995-2006) using the terms: TMC114, darunavir, resistance, screening, selection, ARV therapy, HIV and HAART [9].

References