Harnessing the Therapeutic Potential and Biological Activity of Antiviral Peptides.

Peptides are ideal candidates for the development of antiviral therapeutics due to their specificity, chemical diversity and potential for highly potent, safe, molecular interventions. By restricting conformational freedom and flexibility, cyclic peptides frequently increase peptide stability. Viral targets are often very challenging as their evasive strategies for infectivity can preclude standard therapies.

Macrocyclic Control in Helix Mimetics.

The α-helix is the most commonly found natural secondary structure in proteins and is intrinsic to many protein-protein interactions involved in important biological functions. Novel peptides designed to mimic helices found in nature employ a variety of methods to control their structure. These approaches are significant due to potential applications in developing new therapeutic agents and materials.

Head-to-Tail Cyclic Peptide Inhibitors of the Interaction between Human von Willebrand Factor and Collagen.

The development of peptide-based therapeutics is on the rise, with macrocyclic compounds providing the added stability and drug-like characteristics sought after. Currently, therapies and preventatives for pathogenic thrombosis target platelet interactions at the site of the clot and have many complications. Herein we describe novel cyclic peptides as moderate inhibitors of the protein-protein interaction between von Willebrand factor (vWF) and collagen that initiates blood clot formation.

Salt-bridging effects on short amphiphilic helical structure and introducing sequence-based short beta-turn motifs.

Determining the minimal sequence necessary to induce protein folding is beneficial in understanding the role of protein-protein interactions in biological systems, as their three-dimensional structures often dictate their activity. Proteins are generally comprised of discrete secondary structures, from α-helices to β-turns and larger β-sheets, each of which is influenced by its primary structure. Manipulating the sequence of short, moderately helical peptides can help elucidate the influences on folding.

Rational design of topographical helix mimics as potent inhibitors of protein-protein interactions.

Protein-protein interactions encompass large surface areas, but often a handful of key residues dominate the binding energy landscape. Rationally designed small molecule scaffolds that reproduce the relative positioning and disposition of important binding residues, termed "hotspot residues", have been shown to successfully inhibit specific protein complexes. Although this strategy has led to development of novel synthetic inhibitors of protein complexes, often direct mimicry of natural amino acid residues does not lead to potent inhibitors.

The role of primary sequence in helical control compared across short α- and β(3)-peptides.

α-helices are the most common form of secondary structure found in proteins. In order to study controlled protein folding, as well as manipulate the interface of helical peptides with targets in protein-protein interactions, many techniques have been developed to induce and stabilize α-helical structure in short synthetic peptides. Furthermore, short, non-natural β-peptides have been established that fold into predictable 14-helices that mimic α-helical structure.

A comparative protease stability study of synthetic macrocyclic peptides that mimic two endocrine hormones.

Peptide therapeutics have traditionally faced many challenges including low bioavailability, poor proteolytic stability and difficult cellular uptake. Conformationally constraining the backbone of a peptide into a macrocyclic ring often ameliorates these problems and allows for the development of a variety of new drugs. Such peptide-based pharmaceuticals can enhance the multi-faceted functionality of peptide side chains, permitting the peptides to bind cellular targets and receptors necessary to impart their role, while protecting them from degrading cellular influences.

Mini review: protein-protein interactions in transcription: a fertile ground for helix mimetics.

Designed ligands that inhibit protein-protein interactions involved in gene expression are valuable as reagents for genomics research and as leads for drug discovery efforts. Selective modulation of protein-protein interactions has proven to be a daunting task for synthetic ligands; however, the last decade has seen significant advances in inhibitor design, especially for helical protein interfaces. This review discusses examples of transcriptional complexes targeted by designer helices.

Making strides in peptide-based therapeutics.

In a recent report published in PNAS, Gellman and coworkers describe the design, characterization, and potent activity of alpha/beta-peptides that mimic a long alpha helix involved in HIV viral entry.

Beta-peptides with improved affinity for hDM2 and hDMX.

We previously described a series of 3(14)-helical beta-peptides that bind the hDM2 protein and inhibit its interaction with a p53-derived peptide in vitro. Here we present a detailed characterization of the interaction of these peptides with hDM2 and report two new beta-peptides in which non-natural side chains have been substituted into the hDM2-recognition epitope. These peptides feature both improved affinity and inhibitory potency in fluorescence polarization and ELISA assays.

Relationship between salt-bridge identity and 14-helix stability of beta3-peptides in aqueous buffer.

We report a systematic analysis of the relationship between salt bridge composition and 14-helix structure within a family of model beta-peptides in aqueous buffer. We find an inverse relationship between side-chain length and the extent of 14-helix structure as judged by CD. Introduction of a stabilizing salt bridge pair within a previously reported beta-peptide ligand for hDM2 led to changes in structure that were detectable by NMR.

beta-Peptides as inhibitors of protein-protein interactions.

We became interested several years ago in exploring whether 14-helical beta-peptide foldamers could bind protein surfaces and inhibit protein-protein interactions, and if so, whether their affinities and specificities would compare favorably with those of natural or miniature proteins. This exploration was complicated initially by the absence of a suitable beta-peptide scaffold, one that possessed a well-defined 14-helical structure in water and tolerated the diverse sequence variation required to generate high-affinity protein surface ligands. In this perspective, we describe our approach to the design of adaptable beta-peptide scaffolds with high levels of 14-helix structure in water, track the subsequent development of 14-helical beta-peptide protein-protein interaction inhibitors, and examine the potential of this strategy for targeting other therapeutically important proteins.