Syntenin-targeted peptide blocker inhibits progression of cancer cells

摘要: Abstract The multidomain adaptor protein syntenin is known to mediate cancer cell metastasis and invasion through its tandem PDZ1 PDZ2 domains, leading the postulation that PDZ may serve as a potential drug target for treatment. Here we report development of high-affinity peptide blockers domain, elucidate blocking correlates with inhibition migration spreading. Two strategies are employed derive from low-affinity natural binding peptides: first, dimerization C termini syntenin-binding peptides confers dimer much higher affinity than monomers; second, unnatural amino acid substitution at P-1 P-2 positions PDZ-binding sequence increases affinity. Through several rounds optimization, discovered dimeric binds tightly dissociation constant 0.21 μM based on fluorescence polarization measurement. inhibits high-expression human cells attenuating ERK phosphorylation MAPK kinase pathway. This work showcases an effective strategy blocker proteins, which resulted in syntenin-targeted antagonist pharmaceutical values treatment over-expressing cancers.