A designed zinc-finger transcriptional repressor of phospholamban improves function of the failing heart.

ABSTRACT: Selective inhibition of disease-related proteins underpins the majority of successful drug-target interactions. However, development of effective antagonists is often hampered by targets that are not druggable using conventional approaches. Here, we apply engineered zinc-finger protein transcription factors (ZFP TFs) to the endogenous phospholamban (PLN) gene, which encodes a well validated but recalcitrant drug target in heart failure. We show that potent repression of PLN expression can be achieved with specificity that approaches single-gene regulation. Moreover, ZFP-driven repression of PLN increases calcium reuptake kinetics and improves contractile function of cardiac muscle both in vitro and in an animal model of heart failure. These results support the development of the PLN repres

SUBMITTER: Zhang HS 

PROVIDER: S-EPMC3412484 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature