RESUMO
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.
Assuntos
Fármacos Anti-HIV/química , Antígenos CD4/metabolismo , HIV-1/efeitos dos fármacos , Oxalatos/química , Piperidinas/química , Pirróis/química , Tiazóis/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Fusão Celular , Linhagem Celular , Proteína gp120 do Envelope de HIV/química , Proteína gp120 do Envelope de HIV/metabolismo , Transcriptase Reversa do HIV/metabolismo , HIV-1/isolamento & purificação , HIV-1/fisiologia , Humanos , Ligação de Hidrogênio , Modelos Moleculares , Conformação Molecular , Oxalatos/síntese química , Oxalatos/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Conformação Proteica , Pirróis/síntese química , Pirróis/farmacologia , Receptores CCR5/metabolismo , Receptores CXCR4/metabolismo , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologia , Internalização do Vírus/efeitos dos fármacosRESUMO
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.
