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In Vitro Antiviral Activity and Cross-Resistance Profile of PL-100, a Novel Protease Inhibitor of Human Immunodeficiency Virus Type 1

Serge Dandache,^1, Guy Sévigny,^1, Jocelyn Yelle,¹ Brent R. Stranix,¹ Neil Parkin,² Jonathan M. Schapiro,³ Mark A. Wainberg,⁴ and Jinzi J. Wu^1*

Ambrilia Biopharma, Incorporated, Verdun, Quebec, Canada,¹ Monogram Biosciences, South San Francisco, California,² National Hemophilia Center, Tel Hashomer, Israel,³ McGill University AIDS Centre, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada⁴

Received 1 February 2007/ Returned for modification 9 March 2007/ Accepted 10 July 2007

Despite the success of highly active antiretroviral therapy, the current emergence and spread of drug-resistant variants of human immunodeficiency virus (HIV) stress the need for new inhibitors with distinct properties. We designed, produced, and screened a library of compounds based on an original L-lysine scaffold for their potentials as HIV type 1 (HIV-1) protease inhibitors (PI). One candidate compound, PL-100, emerged as a specific and noncytotoxic PI that exhibited potent inhibition of HIV-1 protease and viral replication in vitro (K_i, 36 pM, and 50% effective concentration [EC₅₀], 16 nM, respectively). To confirm that PL-100 possessed a favorable resistance profile, we performed a cross-resistance study using a panel of 63 viral strains from PI-experienced patients selected for the presence of primary PI mutations known to confer resistance to multiple PIs now in clinical use. The results showed that PL-100 retained excellent antiviral activity against almost all of these PI-resistant viruses and that its performance in this regard was superior to those of atazanavir, amprenavir, indinavir, lopinavir, nelfinavir, and saquinavir. In almost every case, the increase in the EC₅₀ for PL-100 observed with viruses containing multiple mutations in protease was far less than that obtained with the other drugs tested. These data underscore the potential for PL-100 to be used in the treatment of drug-resistant HIV disease and argue for its further development.

Published ahead of print on 16 July 2007.

S.D. and G.S. contributed equally to this work.