RESUMEN
Earlier we reported the discovery and design of NBD-556 and their analogs which demonstrated their potential as HIV-1 entry inhibitors. However, progress in developing these inhibitors has been stymied by their CD4-agonist properties, an unfavorable trait for use as drug. Here, we demonstrate the successful conversion of a full CD4-agonist (NBD-556) through a partial CD4-agonist (NBD-09027), to a full CD4-antagonist (NBD-11021) by structure-based modification of the critical oxalamide midregion, previously thought to be intolerant of modification. NBD-11021 showed unprecedented neutralization breath for this class of inhibitors, with pan-neutralization against a panel of 56 Env-pseudotyped HIV-1 representing diverse subtypes of clinical isolates (IC50 as low as 270 nM). The cocrystal structure of NBD-11021 complexed to a monomeric HIV-1 gp120 core revealed its detail binding characteristics. The study is expected to provide a framework for further development of NBD series as HIV-1 entry inhibitors for clinical application against AIDS.
Asunto(s)
Fármacos Anti-VIH/química , Antígenos CD4/metabolismo , VIH-1/efectos de los fármacos , Oxalatos/química , Piperidinas/química , Pirroles/química , Tiazoles/química , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Fusión Celular , Línea Celular , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/metabolismo , Transcriptasa Inversa del VIH/metabolismo , VIH-1/aislamiento & purificación , VIH-1/fisiología , Humanos , Enlace de Hidrógeno , Modelos Moleculares , Conformación Molecular , Oxalatos/síntesis química , Oxalatos/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Conformación Proteica , Pirroles/síntesis química , Pirroles/farmacología , Receptores CCR5/metabolismo , Receptores CXCR4/metabolismo , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacología , Internalización del Virus/efectos de los fármacosRESUMEN
Linking decyl-triphenyl-phosphonium to fluorescein yields a fluorescent probe that accumulates in energized mitochondria, facilitates proton transfer across membranes and stimulates mitochondrial respiration. This features a mitochondria-targeted uncoupler, being of potential interest for therapeutic use against oxidative stress-related diseases.