RESUMEN
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.
Asunto(s)
Antivirales/farmacología , Carbamatos/farmacología , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , Sulfonamidas/farmacología , Antivirales/química , Carbamatos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Farmacorresistencia Viral/genética , Genotipo , Inhibidores de la Proteasa del VIH/química , VIH-1/química , VIH-1/genética , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mutación , Fenotipo , Sulfonamidas/química , Proteínas Virales/genética , Proteínas Virales/metabolismoRESUMEN
A series of lysine sulfonamide analogues bearing Nepsilon-acyl aromatic amino acids were synthesized using an efficient synthetic route. Evaluation of these novel protease inhibitors revealed compounds with high potency against wild-type and multiple-protease inhibitor-resistant HIV viruses.
Asunto(s)
Aminoácidos/química , Fármacos Anti-VIH/farmacología , Inhibidores de la Proteasa del VIH/farmacología , Lisina/química , Sulfonamidas/farmacología , Acilación , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Línea Celular , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , VIH/efectos de los fármacos , Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/química , Humanos , Técnicas In Vitro , Lisina/análogos & derivados , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
A series of lysine sulfonamide analogues bearing a Nepsilon-benzylic ureas was synthesized using both solution-phase and solid-phase approaches. A novel synthetic route of Nalpha-(alkyl)-Nalpha-(sulfonamides)lysinol using alpha-amino-caprolactam was developed. Evaluation of these novel protease inhibitors revealed compounds with high potency against wild-type HIV virus.
Asunto(s)
Inhibidores de la Proteasa del VIH/síntesis química , VIH/efectos de los fármacos , Lisina , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Inhibidores de la Proteasa del VIH/farmacología , Cinética , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of Nalpha-isobutyl-Nalpha-arylsulfonamido-(Nepsilon acyl) lysine and lysinol derivatives were prepared and evaluated as inhibitors of HIV protease and wild type virus. A simple original synthesis was devised to form Nalpha-(arylsulfonamide)-Nalpha-isobutyl lysine, which could be easily acylated with carboxylic acids at the Nepsilon position. A two-atom spacer was found to be optimal between this acyl group and a phenyl yielding compounds of sub-nanomolar potency on purified enzyme.
Asunto(s)
Inhibidores de la Proteasa del VIH/farmacología , Lisina/análogos & derivados , Lisina/farmacología , Sulfonamidas/farmacología , Diseño de Fármacos , Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/química , Lisina/síntesis química , Lisina/química , Modelos Moleculares , Conformación Molecular , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
The synthesis and structure-activity relationships of HIV protease inhibitors derived from carbohydrate alditols are discussed. We disclose a new series of 1,2,5,6-tetra-O-alkyl-D-mannitol exhibiting sub-micromolar activity against HIV-protease. This series of inhibitors are non-nitrogen containing HIV-protease inhibitors and they are readily prepared in a few chemical steps from inexpensive commercially available starting materials.