title: In vitro antiviral activity and cross-resistance profile of PL-100, a novel protease inhibitor of human immunodeficiency virus type 1.
abstract: 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), approximately 36 pM, and 50% effective concentration [EC(50)], approximately 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 EC(50) 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.
authors.affiliation: Ambrilia Biopharma, Inc., 1000 Chemin du Golf, Verdun, Quebec, Canada H3E 1H4. jwu@ambrilia.com.
authors.forename: Serge
authors.initials: S
authors.lastname: Dandache
authors.forename: Guy
authors.initials: G
authors.lastname: Sévigny
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Yelle
authors.forename: Brent R
authors.initials: BR
authors.lastname: Stranix
authors.forename: Neil
authors.initials: N
authors.lastname: Parkin
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schapiro
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
authors.forename: Jinzi J
authors.initials: JJ
authors.lastname: Wu
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D024882:Drug Resistance, Viral / Q000235:genetics; D005838:Genotype; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009154:Mutation; D010641:Phenotype; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D017320:HIV Protease Inhibitors; C525732:PL 100; D013449:Sulfonamides; D014764:Viral Proteins