Peptides Containing β-Amino Acid Patterns: Challenges and Successes in Medicinal Chemistry

Abstract

The construction of bioactive peptides using β-amino acid-containing sequence patterns is a very promising strategy to obtain analogues that exhibit properties of high interest for medicinal chemistry applications. β-Amino acids have been shown to modulate the conformation, dynamics, and proteolytic susceptibility of native peptides. They can be either combined with α-amino acids by following specific patterns, which results in backbone architectures with well-defined orientations of the side chain functional groups, or assembled in de novo-designed bioactive β- or α,β-peptidic sequences. Such peptides display various biological functions, including antimicrobial activity, inhibition of protein-protein interactions, agonism/antagonism of GPCR ligands, and anti-angiogenic activity.

C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies

“…Especially, those composed of functionalized cyclobutane (Declerck 2011;Gorrea 2012;Pohl 2013;Altmayer-Henzien 2015), cyclopentane and cyclohexane (Martinek 2012) derivatives have biological importance and perspectives (Cabrele 2014;Mándity 2015). To a great extent, the introduced none natural amino acid derivatives (e.g.…”

“…Reduced mobility, if the conformation is carefully designed could increase binding ability of the polypeptide to other macromolecules, receptors and thus enhance bioactivity. Cis and trans stereoisomers of both 2-aminocyclopentanecarboxylic acid (ACPC) and 2-aminocyclohexanecarboxylic acid (ACHC) derivatives are now extensively used to design chimeras in conjunction with acyclic γ-and/or δ-amino acid residues (Cabrele 2014;Giuliano 2013). However, as both ACPC and ACHC derivatives are hydrophobic, their hydrophilic related compounds would be of great relevance, not yet fully explored (Hetényi 2009).…”

Origin of problems related to Staudinger reduction in carbopeptoid syntheses

“…The enzyme resistance of α/β-peptides, coupled to their inherent feature of self-assembly (Beke et al 2008) and a propensity for forming nanostructures, initiated stud-ies of particular importance, with different β-amino acids of modified side chains used as protein mimetics (Cheng et al 2001;Hecht and Huc 2007;Horne and Gellman 2008;Pilsl and Reiser 2011;Guichard and Huc 2011;Martinek and Fülöp 2012;Cabrele et al 2014;Mándity and Fülöp 2015). β-Amino acid building blocks of cyclic skeleton are of special interest, as the ring structure puts constraint on the central θ-backbone torsional angle adjacent to ϕ and ψ and thus stabilizes specific secondary structural elements (Beke et al 2004).…”

Molecular mimicry of conformationally diverse β-sheets by using α/β-peptide foldamers

“…Among aliphatic foldamers, -peptides that are homologs of the natural -peptides, gained high interest in medicinal chemistry applications. [3][4][5] -Peptides are promising alternatives for natural peptides or biopharmaceuticals, because they are able to display well-folded structures using short sequences, and the placement of functional groups can be controlled. In comparison with a 150 kDa therapeutic antibody, these foldamers can exhibit folded structure and similar interaction surface even at a size of 3-5 kDa.…”

“…-Peptide foldamers were successfully applied in molecular recognition processes targeting proteins and membranes, but these results were achieved mainly by using helical secondary structures. [3][4][5] The mimicry of -sheets therefore requires further investigations, only a few sheet-like structures are known with biological activity. [6][7][8][9][10][11][12] Our goal was to establish design strategies for conformationally diverse -sheet folding systems by using -peptide foldamers based on a selected peptide participating in proteinprotein and membrane interactions.…”