Design of a novel polydactyl zinc finger with binding specificity for the proximal promoter region of PLN in the proposed treatment of cardiomyopathy.

Abstract

Heart disease is the leading cause of death worldwide. Cardiomyopathy, a form of heart disease, is one of the many areas of clinical interest and is characterized as a disease of the heart myocardium. Phospholamban (PLN) is one of the many proteins linked with this disease. Its primary function in the cell is the inhibition of the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2) calcium transporter located in muscle tissue. There is a direct causal link between when PLN is over-expressed, super-inhibitory or non-existent and the development of various forms of cardiomyopathy. In an effort to counteract the development of cardiomyopathy, we have designed a novel zinc finger protein named Dandy, which specifically binds form the –77 to -95 region of the proximal promoter of the PLN gene. This protein is expected to transiently block the binding of the NFY promoter and thus, the initiation of transcription. Blocking initiation of transcription should result in an overall decrease in the concentration of PLN. Dandy is a zinc finger protein made up of two three-fingered peptides. It recognizes a 18 bp sequence with a 1 bp gap in the middle. Tertiary structure predictions of Dandy show that the protein has the intended structure of the design. More clinical research into the specific binding interactions will need to be completed before in vivo function and overall efficacy of Dandy is elucidated.