Sophistication of foldamer form and function in vitro and in vivo

doi:10.1016/j.cbpa.2007.09.009

Current Opinion in Chemical Biology

Volume 11, Issue 6, December 2007, Pages 685-692

https://doi.org/10.1016/j.cbpa.2007.09.009 Get rights and content

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.

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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^*: These authors contributed equally to this work.

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Sophistication of foldamer form and function in vitro and in vivo

Introduction

Section snippets

Gaining entry – all in the charge

Mixed α/β-peptides

Foldamers take shape

Conclusions

References and recommended reading

Acknowledgements

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The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: peptoid molecular transporters

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Preparation of N-Fmoc-protected β₂- and β₃-amino acids and their use as building blocks for the solid-phase synthesis of β-peptides

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