Cyclic Tau-derived peptides for stabilization of microtubules

Abstract

The cyclization of peptides is a valuable strategy for the development of binding motifs to target proteins with improved affinity. Microtubules (MTs) are important targets for therapeutics, and a variety of MT-targeted drugs and peptides have recently been developed. We have previously designed a Tau-derived peptide (TP) that binds to the interior of MTs. In the present study, the development of a cyclic TP (TCP) for enhanced binding to tubulin and the stabilization of MTs are described. The fluorescently labeled cyclic peptide containing three glycine linkers (TCP3-TMR) exhibited a remarkably enhanced binding affinity to tubulin. The cyclic peptide was also demonstrated to stabilize MTs by enhancing polymerization and reducing depolymerization. Moreover, MTs were effectively formed by the treatment of cyclic peptides in the presence of guanosine triphosphate (GTP), while the linear peptide showed no such effect. These findings indicate that TCP is a useful binding motif that can stabilize MTs and is valuable for various therapeutic and material applications. Microtubules (MTs) consisting of tubulins are important targets of drugs for MT-related diseases. We have previously designed a linear Tau-derived peptide (TP) that binds to the interior of MTs. In this article, a cyclic TP (TCP) was developed for enhanced binding to tubulin and stabilization of MTs. The fluorescently labeled TCP exhibited a remarkably enhanced binding affinity to tubulin compared to the linear TP. The stabilization of MTs by binding of TCP was demonstrated, such as formation of typically unstable MTs in the presence of guanosine triphosphate.