Constraining Cyclic Peptides To Mimic Protein Structure Motifs

Abstract

Many proteins exert their biological activities through small exposed surface regions called epitopes that are folded peptides of well-defined three-dimensional structures. Short synthetic peptide sequences corresponding to these bioactive protein surfaces do not form thermodynamically stable protein-like structures in water. However, short peptides can be induced to fold into protein-like bioactive conformations (strands, helices, turns) by cyclization, in conjunction with the use of other molecular constraints, that helps to fine-tune three-dimensional structure. Such constrained cyclic peptides can have protein-like biological activities and potencies, enabling their uses as biological probes and leads to therapeutics, diagnostics and vaccines. This Review highlights examples of cyclic peptides that mimic three-dimensional structures of strand, turn or helical segments of peptides and proteins, and identifies some additional restraints incorporated into natural product cyclic peptides and synthetic macrocyclic peptidomimetics that refine peptide structure and confer biological properties.

Direct Modulation of Small GTPase Activity and Function

“…[131,132,134] Thef irst generation of these inhibitors suffered from inefficient cell penetration, but permeability was improved in av ery recent second generation of cyclorasins. [134] Their performance in in vivo studies needs to be investigated for assessment of the full potential of these promising inhibitors of Ras-effector interactions.A saconsequence of their larger interaction surfaces,m acrocycles and stabilized structured peptides are highly interesting compound classes for PPI inhibition, [160] and might provide sufficient binding affinity and selectivity for small GTPase targeting. Thei dentification of the stapled peptide StRIP3 (41)a sa ni nhibitor of Rab8-effector interactions [136] also indicates that such modified macromolecules can act as effective modulators of activated small GTPases.…”

Beyond Natural Limitations: Long‐Range Influence of Non‐Natural Flexible and Rigid β‐Turn Mimetics in a Native β‐Hairpin Motif

“…These highly sensitive and selective molecular recognition processes are mediated by relatively small exposed surface regions of proteins or peptides with welldefined shapes called epitopes. [1] To address a target protein's surface for a protein-protein type molecular recognition process in biological and medicinal chemistry, the epitopes involved need to be mimicked by small, but wellstructured, synthetically accessible protein fragments. [2] Unfortunately, the excised peptide fragment, detached from its protein environment, loses its epitope character and binding specificity in water due to competing hydrogen bonding of the peptide backbone with the solvent.…”

Macrocyclic Cell Penetrating Peptides: A Study of Structure-Penetration Properties

“…12,13,[27][28][29][30][31][32] In this context, macrocyclization is a well established approach to simultaneously rigidify a peptide backbone, modulate its structure-activity, improve its proteolytic stability and reduce the entropic cost of macrocycle-target interactions. [33][34][35][36] These attributes are attractive to improve the properties of CPPs, [37][38][39][40][41][42][43][44] thus macrocyclization and backbone rigidification of CPPs was expected to improve cellular uptake and stability, as well as to provide a means to discriminate among different cell types. Indeed, it has been proposed that guanidinium groups are forced into maximally distant positions by cyclization, increasing membrane contacts and leading to enhanced cellular penetration.…”