Branched Peptides for the Modulation of Protein-Protein Interactions: More Arms are Better than One?

Abstract

Combinatorial peptide libraries from synthetic or biological sources have been largely used in the last two-decades with the aim of identifying bioactive peptides that specifically bind proteins and modulate their interactions with other protein partners. Differently from biological libraries, synthetic methods allow the development of different kinds of libraries based on two main characteristics: i) the use of building blocks and chemical bonds different from those naturally occurring and ii) the possibility of designing scaffolds with non-linear shapes, as cyclic and branched structures. These two features, alone or in combination, have increased the chemical and structural diversity of peptide libraries expanding the offer of collections for the screenings. Here we describe our and other experiences with branched peptides and the results obtained in the last fifteen years. These clearly indicate how the use of short multimerized peptides can represent a successful approach for different applications ranging from affinity chromatography to the modulation of protein-protein interactions in different biological contexts.

Features of protein–protein interactions that translate into potent inhibitors: topology, surface area and affinity

“…Similarly, peptidomimetics, cyclic peptides and stapled peptides are being increasingly used to inhibit PPIs (Refs 35, 36). These ligands mimic natural protein–protein contacts by presenting multiple amino acid side chains from architecturally complex cores (Refs 37, 38, 39, 40, 41). Finally, small-molecule–protein hybrids have been developed to artificially increase apparent molecular mass and target the most difficult PPIs (Refs 42, 43).…”

Trimers Conjugated to Fibrin Hydrogels Promote Salivary Gland Function

“…Specifically, multimeric peptides are reported to be critical for increasing recognition of cell surfaces while promoting tissue stability (Grove et al 2008). Likewise, multimerization of a bioactive monomeric peptide enhances interaction between target surfaces and peptides; however, multimeric peptides do not create new recognition sites (e.g., RGD will always bind to SH3 domains; Ruvo et al 2011). Thus, our results could be a consequence of an enhanced interaction of the trimeric RGD and α 5 β 1 , α 8 β 1 , α V β 1 , α IIb β 3 , α V β 3 , α V β 5 , and α V β 6 integrin receptors (Ruoslahti 1996) with an enhanced contact of the trimeric YIGSR and α 3 β 1 , α 4 β 1 , and α 6 β 1 integrin receptors (Maeda et al 1994).…”

Enhanced Membrane-tethered Mucin 3 (MUC3) Expression by a Tetrameric Branched Peptide with a Conserved TFLK Motif Inhibits Bacteria Adherence*

“…The linear, cyclic, multimeric, and branched structures have been used as scaffolds into which natural or non-natural amino acids have been inserted to increase the chemical diversity or to achieve a more rigid conformation and more stable structures (17). Several reports have demonstrated that increasing the copy number of a precursor peptide by multimerization is a simple and effective way to enhance immunogenicity, affinity, and stability.…”

“…Recently, multimeric peptides have been described in the literature as an obvious solution to increase peptide size and affinity while maintaining the original amino acid sequence (17)(18)(19), and this approach is a key strategy to increase recognition surfaces and/or stability. Increasing the peptide size also increases the difficulty of identifying peptides with high affinity and selectivity; however, multimeric peptides comprising simple branched structures and a short arm may offer an optimal compromise between molecular size and the ease of preparation, yield, and purity of the final product.…”