Interference of phosphatase calcineurin and its substrate nuclear factor of activated T cells (NFAT) interaction has therapeutic effect in the treatment of transplant rejection, autoimmune diseases and cardiovascular disorders. Cyclosporin A, a natural cyclic peptide drug, functions by inhibiting calcineurin activity, also results in side effect. A peptide inhibitor VIVIT blocking the calcineurin/NFAT interaction without compromising the phosphatase activity is limited by its potency, stability and cell permeability. Our goal is to develop cyclic peptide inhibitors that retain the selectivity of VIVIT against NFAT, but with more pharmatheutical properties like Cyclosporin A. A robust methodology has been developed in our lab for large cyclic peptide library screening including: magnetic facilitated screening, solution phase binding determination without resynthesis and high throughput sequencing. A cyclic peptide library based on the VIVIT scaffold with a diversity of 1010 was synthesized and screened against calcineurin. The promising hits will be tested against calcineurin/NFAT interaction and further improved.

High throughput screening of cyclic peptides library to identify inhibitors against calcineurin/NFAT interaction

240th National Meeting (2010)

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