Generation of a cell-permeable cycloheptapeptidyl inhibitor against the peptidyl–prolyl isomerase Pin1

Abstract

Cyclic peptides are capable of binding and modulating challenging drug targets including protein-protein interactions. However, their lack of membrane permeability prevents their applications against intracellular targets. In this study, we show that it is possible to design a cell-permeable and biologically active cycloheptapeptide inhibitor against intracellular enzyme peptidyl-prolyl isomerase Pin1 by integrating cell-penetrating and target-binding sequences.

Hydrolysis, polarity, and conformational impact of C-terminal partially fluorinated ethyl esters in peptide models

“…This result also suggests that the hydrolysis rate of a C-terminal ester in peptides can be well tailored by installing proximal charges in the molecule. This conclusion is of particular importance due to growing interest in modifying potential peptide therapeutics with positively charged residues for improved cell permeability [ 92 ]. Though, the charge-induced hydrolysis acceleration from the proximal lysine charge ( 9b , 10b vs 8b , factor ≈ 30) is lower than the α-NH 2 /NH 3 + hydrolysis acceleration in the classical studies of α-amino acid esters (factor ≈ 100–150) [ 58 ].…”

Function of PIN1 in Cancer Development and Its Inhibitors as Cancer Therapeutics

“…A cyclic peptide derivative with increased cell permeable ability repressed the activity of PIN1 (IC50 = 32 nM) and inhibited the BT-474 breast cancer cell proliferation (Liu et al, 2010). Treatment of 100 nM of this peptide in cancer cell lines (HeLa and BT-474) increases the levels of PML and SMRT, and inhibits intracellular PIN1 activity (Liu et al, 2010;Bedewy et al, 2017). A major flavonoid of green tea, epigallocatechin 3 gallate (EGCG) is widely known as chemo-preventive compound for cancer and one of PIN1 inhibitor.…”

Discovery of Membrane-Permeating Cyclic Peptides via mRNA Display

“…5,8,[32][33][34][35][36][37][38] Peptides are particularly attractive for this application: they can be produced at large volumes affordably, are safety and biocompatibility, and can act as both penetrating agents and probes for manipulating PPIs and NPIs. 39 The screening of peptide libraries has been shown to be a powerful tool for the identification of cell-and tissue-permeating peptides. 40 The underlying premise of combinatorial screening is that a peptide sequence possessing any desired bioactivity can be identified, provided that the library has high diversity, and the screening process is appropriately designed and conducted through a sufficient number of iterations.…”