TMC114, a Novel Human Immunodeficiency Virus Type 1 Protease Inhibitor Active against Protease Inhibitor-Resistant Viruses, Including a Broad Range of Clinical Isolates

Abstract

The purpose of this study was to characterize the antiviral activity, cytotoxicity, and mechanism of action of TMC114, a novel human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI). TMC114 exhibited potent anti-HIV activity with a 50% effective concentration (EC 50 ) of 1 to 5 nM and a 90% effective concentration of 2.7 to 13 nM. TMC114 exhibited no cytotoxicity at concentrations up to 100 M (selectivity index, >20,000). All viruses in a panel of 19 recombinant clinical isolates carrying multiple protease mutations and demonstrating resistance to an average of five other PIs, were susceptible to TMC114, defined as a fold change in EC 50 of <4. TMC114 was also effective against the majority of 1,501 PI-resistant recombinant viruses derived from recent clinical samples, with EC 50 s of <10 nM for 75% of the samples. In sequential passage experiments using HIV-1 LAI, two mutations (R41T and K70E) were selected. One selected virus showed a 10-fold reduction in susceptibility to TMC114, but <10-fold reductions in susceptibility to the current PIs (atazanavir was not assessed), except saquinavir. 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. There was no evidence of antagonism between TMC114 and any currently available PIs or reverse transcriptase inhibitors. Combinations with ritonavir, nelfinavir, and amprenavir showed some evidence of synergy. These results suggest that TMC114 is a potential candidate for the treatment of both naïve and PI-experienced patients with HIV.

Potent Inhibition of HIV-1 Replication by Novel Non-peptidyl Small Molecule Inhibitors of Protease Dimerization

“…The emergence of DRV-resistant HIV-1 seems to be substantially delayed both in vitro (45) and clinical settings (46,47). One can speculate that DRV inhibits protease dimerization, leaving catalytically inert monomers, but if certain monomers escape from DRV and achieve the mature dimer form, DRV again blocks the proteolytic action of mature (wildtype and mutant) protease as a conventional protease inhibitor.…”

New Validated Rp-HPLC Method for the Estimation of Darunavir in Bulk and Its Dosage Form

“…Proposed method is validated as per ICH guideline for Analytical Procedures 6 . Recent studies suggested that protease inhibitors like Darunavir, Ritonavir, Nelfinavir showed no evidence of antagonism when used with TMC114 7,8 . Literature survey reveals that there are reports describing the determination of Darunavir in Plasma using liquid chromatography coupled with Tandem Mass Spectroscopy 9 , few HPTLC method for determination of Darunavir in rat plasma and in tablet dosage form its application to pharmacokinetic studies 10,11 , infrared spectroscopy method for determination of Darunavir in tablets 12 , and few RP-HPLC and Spectrophotometric methods 13,14 .…”

Effectiveness of tipranavir versus darunavir as a salvage therapy in HIV-1 treatment-experienced patients

“…The development of new PIs with significant antiviral activity in individuals with extensive class resistance has emerged as an issue of paramount importance in the field of HIV therapy [2,3]. Tipranavir (TPV) and darunavir (DRV) are the first PIs that were developed for the management of infection caused by PI-resistant viruses, and each of these drugs exhibited potent in vivo and in vitro activity against HIV-1 strains with accumulated multiple mutations associated with resistance to this class of drugs [4]. Each of these drugs has been shown to be superior to equivalent PIs in randomized controlled trials of treatment-experienced patients [5,6].…”