This Article Full Text (PDF) Other Versions of this Article: AAC.00149-07v1 51/11/4036    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Dandache, S. Articles by Wu, J. J. Search for Related Content PubMed PubMed Citation Articles by Dandache, S. Articles by Wu, J. J.

 Previous Article  |  Next Article 

Antimicrob. Agents Chemother. doi:10.1128/AAC.00149-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

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

	Abstract

Despite the success of HAART (highly active anti-retroviral 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 have designed, produced and screened a library of compounds based on an original L-lysine scaffold for their potential as HIV-1 protease inhibitors (PI). One candidate compound, PL-100, emerged as a specific and non-cytotoxic PI that exhibited potent inhibition of HIV-1 protease and viral replication in vitro (K_i 36 pM and 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 show 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 each of atazanavir, amprenavir, indinavir, lopinavir, nelfinavir and saquinavir. In almost every case, the fold-change increase in 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.