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Antimicrobial Agents and Chemotherapy, November 2007, p. 4036-4043, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.00149-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Serge Dandache,1,{dagger} Guy Sévigny,1,{dagger} Jocelyn Yelle,1 Brent R. Stranix,1 Neil Parkin,2 Jonathan M. Schapiro,3 Mark A. Wainberg,4 and Jinzi J. Wu1*

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 (Ki, ~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.

* Corresponding author. Mailing address: Ambrilia Biopharma, Inc., 1000 Chemin du Golf, Verdun, Quebec, Canada H3E 1H4. Phone: (514) 732-3206. Fax: (514) 751-2502. E-mail: jwu{at}ambrilia.com

{triangledown} Published ahead of print on 16 July 2007.

{dagger} S.D. and G.S. contributed equally to this work.

Antimicrobial Agents and Chemotherapy, November 2007, p. 4036-4043, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.00149-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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