Sophistication of foldamer form and function in vitro and in vivo
Introduction
Life has evolved for billions of years in large part due to the sophisticated functions of an elite group of biological polymers. Unique in their historical position, biopolymers were long thought to be alone in the world of macromolecules that assume complex three-dimensional structures based solely on their primary sequence. A new field has emerged and flourished thanks to the realization that chemical moieties with unique, non-biological backbones, more popularly known as foldamers, are also capable of higher-ordered structure and function. This often begs the question as to why Nature chose nucleic acids and polypeptides as the vehicles of life. Advances in the foldamer field in recent years are as diverse as the backbones of which they are composed. Applications have ranged from cellular penetration and membrane disruption to discrete molecular recognition, while efforts to control the complex geometric shape of foldamers has entered the realm of tertiary and quaternary structure. This review will provide recent examples of progress in the foldamer field, highlighting the significance of this class of compounds and the advances that have been made towards exploiting their full potential.
Section snippets
Gaining entry – all in the charge
Cell-penetrating peptides (CPPs) have emerged as promising tools for the intracellular delivery of molecules ranging in size from small molecules and peptides to proteins and quantum dots [1, 2, 3, 4, 5]. Previously reported CPPs, such as the 9-aa HIV-1 Tat peptide [6], penetratin (16-aa) [7], and HSV-1 VP22 (34-aa) [8] are cationic and/or amphipathic, often with high α-helical propensity [9]. Sequences rich in arginine are particularly effective – in fact, short oligo-arginine peptides are
Mixed α/β-peptides
Several recent reports have documented the utility of β-peptides in biological applications, highlighting their potential as inhibitors of intramolecular or intermolecular protein–protein interactions. The substitution of β-amino acids into α-peptides has been reviewed previously [28], but new work by Muller and co-workers [29] expands the idea to the incorporation of aza-β3-amino acids, which contain nitrogen in the backbone, into a model peptide that mimics a CD4 T cell epitope. These
Foldamers take shape
Natural biopolymers fold with fidelity, can exist as oligomers or discrete complexes, and possess kinetic and thermodynamic signatures that distinguish them from non-biological polymers and smaller molecules. Significant progress has been made in the past year towards foldamers that assemble cooperatively into discrete tertiary and quaternary structures, paving the way towards foldamers with sophisticated function.
Conclusions
Within the last year, significant advances have been made towards extending the diverse applications of foldamers and fully understanding their utility and versatility. These molecules are of particular interest due to the unique structures formed from the monomers of which they are composed. Initial work was focused on fully characterizing their structural features, but recent reports have highlighted their ability to enter cells, to recognize protein surfaces, and to even assemble into
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
AS thanks the National Institutes of Health and the National Foundation for Cancer Research for their generous support of this work. ADB thanks Professors Samuel Gellman, Jean Chielewski and Ivan Huc for figures. CJC thanks Professor Ishwar Radhakrishnan for the atomic coordinates file for the Nspe9 peptoid nonamer. ADB and CJC thank Dr. E. James Petersson for helpful discussion.
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Tailoring peptides and peptidomimetics for targeting protein–protein interactions
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2020, Journal of Organic ChemistryThe relevance of the relative configuration in the folding of hybrid peptides containing β-cyclobutane amino acids and γ-amino-L-proline residues
2017, TetrahedronCitation Excerpt :The intra-residue 6-membered hydrogen bond (Fig. 1) was observed in the β-CBAA in the hybrid peptides containing glycine and GABA residues. Some of these β-CBAAs and the peptides in which they have been incorporated have found application as functional organofibers,13 as organogelators,14 as neuropeptide Y inhibitors15 and as surfactants.16 Proline is a naturally occurring amino acid which is conformationally constrained due to the pyrrolidine ring, and which induces well defined secondary structures in peptides that contain it.17
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These authors contributed equally to this work.