RESUMO
The persistence of a pool of latently HIV-1-infected cells despite combination anti-retroviral therapy treatment is the major roadblock for a cure. The BAF (mammalian SWI/SNF) chromatin remodeling complex is involved in establishing and maintaining viral latency, making it an attractive drug target for HIV-1 latency reversal. Here we report a high-throughput screen for inhibitors of BAF-mediated transcription in cells and the subsequent identification of a 12-membered macrolactam. This compound binds ARID1A-specific BAF complexes, prevents nucleosomal positioning, and relieves transcriptional repression of HIV-1. Through this mechanism, these compounds are able to reverse HIV-1 latency in an in vitro T cell line, an ex vivo primary cell model of HIV-1 latency, and in patient CD4+ T cells without toxicity or T cell activation. These macrolactams represent a class of latency reversal agents with unique mechanism of action, and can be combined with other latency reversal agents to improve reservoir targeting.
Assuntos
Proteínas Cromossômicas não Histona/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Transcrição Gênica/efeitos dos fármacos , Latência Viral/efeitos dos fármacos , Animais , Linhagem Celular , Proteínas Cromossômicas não Histona/metabolismo , HIV-1/crescimento & desenvolvimento , Ensaios de Triagem em Larga Escala , Camundongos , Bibliotecas de Moléculas Pequenas/química , Fatores de Transcrição/metabolismo , Latência Viral/genéticaRESUMO
Synthesis of a potential Src family SH2 domain inhibitor incorporating a 1,4-cis-enediol scaffold is reported. The synthetic route offers straightforward and highly selective access to the enediol and its associated chiral centers. Key steps include stereocontrolled syn-aldol coupling, amide alkynylation, and asymmetric ketone reduction.
RESUMO
L-selectride reduction of a chiral or achiral enone followed by reaction of the resulting enolate with optically active alpha-alkoxy aldehydes proceeded with excellent diastereoselectivity. The resulting alpha,alpha-dimethyl-beta-hydroxy ketones are inherent to a variety of biologically active natural products.