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Antimicrobial Agents and Chemotherapy, June 2005, p. 2314-2321, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2314-2321.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Sandra De Meyer, Hilde Azijn, Dominique Surleraux, Dirk Jochmans, Abdellah Tahri, Rudi Pauwels, Piet Wigerinck, and Marie-Pierre de Béthune*

Tibotec, Gen De Wittelaan L 11B 3, B2800 Mechelen, Belgium

Received 25 May 2004/ Returned for modification 20 July 2004/ Accepted 1 February 2005

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 (EC50) 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 µM (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 EC50 of <4. TMC114 was also effective against the majority of 1,501 PI-resistant recombinant viruses derived from recent clinical samples, with EC50s 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.

* Corresponding author. Mailing address: Tibotec, Gen De Wittelaan L 11B 3, B2800 Mechelen, Belgium. Phone: 32 15 401 240. Fax: 32 15 286 347. E-mail: mdbethun{at}tibbe.jnj.com.

Antimicrobial Agents and Chemotherapy, June 2005, p. 2314-2321, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2314-2321.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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