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?-AApeptides as a New Class of Peptidomimetics.

ABSTRACT: Sequence-specific peptidomimetics are molecules that mimic the structure and function of peptides and proteins. With new backbones and molecular frameworks, peptidomimetics are of considerable interest in addressing challenges encountered in chemical biology and biomedical sciences. Based on the ?-PNA backbone, a new class of peptidomimetics - "?-AApeptides" were recently developed. Both linear and cyclic ?-AApeptides can be synthesized with high efficiency. Compared with ?-peptides, ?-AApeptides are resistant to enzymatic degradation, and amendable to diversification with a variety of chemical groups. Moreover, they could mimic primary and secondary structure, as well as the function of peptides, and show promise in biological applications, such as the development of new agents combating bacteria, cancer, and Alzheimer's disease. A few research outcomes of ?-AApeptides are highlighted in this Concept article, and a future perspective is also proposed.

SUBMITTER: Teng P

PROVIDER: S-EPMC4955406 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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γ-AApeptides as a New Class of Peptidomimetics.

Teng Peng P Shi Yan Y Sang Peng P Cai Jianfeng J

Chemistry (Weinheim an der Bergstrasse, Germany) 20160304 16

Sequence-specific peptidomimetics are molecules that mimic the structure and function of peptides and proteins. With new backbones and molecular frameworks, peptidomimetics are of considerable interest in addressing challenges encountered in chemical biology and biomedical sciences. Based on the γ-PNA backbone, a new class of peptidomimetics - "γ-AApeptides" were recently developed. Both linear and cyclic γ-AApeptides can be synthesized with high efficiency. Compared with α-peptides, γ-AApeptide ...[more]

PMID: 26945679

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Project description:Foldamers have defined and predictable structures, improved resistance to proteolytic degradation, enhanced chemical diversity, and are versatile in their mimicry of biological molecules, making them promising candidates in biomedical and material applications. However, as natural macromolecules exhibit endless folding structures and functions, the exploration of the applications of foldamers remains crucial. As such, it is imperative to continue to discover unnatural foldameric architectures with new frameworks and molecular scaffolds. To this end, we recently developed a new class of peptidomimetics termed ″γ-AApeptides", oligomers of γ-substituted-N-acylated-N-aminoethyl amino acids, which are inspired by the chiral peptide nucleic acid backbone. To date γ-AApeptides have been shown to be resistant to proteolytic degradation and possess limitless potential to introduce chemically diverse functional groups, demonstrating promise in biomedical and material sciences. However, the structures of γ-AApeptides were initially unknown, rendering their rational design for the mimicry of a protein helical domain impossible in the beginning, which limited their potential development. To our delight, in the past few years, we have obtained a series of crystal structures of helical sulfono-γ-AApeptides, a subclass of γ-AApeptides. The single-crystal X-ray crystallography indicates that sulfono-γ-AApeptides fold into unprecedented and well-defined helices with unique helical parameters. On the basis of the well-established size, shape, and folding conformation, the design of sulfono-γ-AApeptide-based foldamers opens a new avenue for the development of alternative unnatural peptidomimetics for their potential applications in chemistry, biology, medicine, materials science, and so on.In this Account, we will outline our journey on sulfono-γ-AApeptides and their application as helical mimetics. We will first briefly introduce the design and synthetic strategy of sulfono-γ-AApeptides and then describe the crystal structures of helical sulfono-γ-AApeptides, including left-handed homogeneous sulfono-γ-AApeptides, right-handed 1:1 α/sulfono-γ-AA peptide hybrids, and right-handed 2:1 α/sulfono-γ-AA peptide hybrids. After that, we will illustrate the potential of helical sulfono-γ-AApeptides for biological applications such as the disruption of medicinally relevant protein-protein interactions (PPIs) of BCL9-β-catenin and p53-MDM2/MDMX as well as the mimicry of glucagon-like peptide 1 (GLP-1). In addition, we also exemplify their potential application in material science. We expect that this Account will shed light on the structure-based design and function of helical sulfono-γ-AApeptides, which can provide a new and alternative way to explore and generate novel foldamers with distinctive structural and functional properties.

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?-AApeptides as a New Class of Peptidomimetics.

Publications

γ-AApeptides as a New Class of Peptidomimetics.

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