Cyclic peptidyl inhibitors of cal-pdz binding domain

Abstract

Described herein, in various embodiments, are peptides comprising: (i) a cyclic cell-penetrating peptide sequence (cCPP) and (ii) a CAL-PDZ binding sequence, which is conjugated, directly or indirectly, to an N-terminus of an amino acid in the cCPP, to a C-terminus of an amino acid on the cCPP, or on a side chain of an amino acid in the cCPP. In other embodiments, the peptides further comprise a physiologically cleavable group, wherein after entering the cell, the physiologically cleavable group is reduced, thereby providing a linear peptide. Without being bound by theory, the inventors discovered that the amino acid sequence in the cCPP, which facilities cytosolic delivery of the CAL-PDZ binding sequence also, surprisingly and unexpectedly, synergistically improves binding of CAL-PDZ binding sequence to the CAL-PDZ binding domain. Additionally, the cCPP sequence may also improve selectivity of the CAL-PDZ binding sequence for the CAL-PDZ domain relative to other PDZ binding domains.