Small and Simple, yet Sturdy: Conformationally Constrained Peptides with Remarkable Properties

Abstract

The sheer size and vast chemical space (i.e., diverse repertoire and spatial distribution of functional groups) underlie peptides’ ability to engage in specific interactions with targets of various structures. However, the inherent flexibility of the peptide chain negatively affects binding affinity and metabolic stability, thereby severely limiting the use of peptides as medicines. Imposing conformational constraints to the peptide chain offers to solve these problems but typically requires laborious structure optimization. Alternatively, libraries of constrained peptides with randomized modules can be screened for specific functions. Here, we present the properties of conformationally constrained peptides and review rigidification chemistries/strategies, as well as synthetic and enzymatic methods of producing macrocyclic peptides. Furthermore, we discuss the in vitro molecular evolution methods for the development of constrained peptides with pre-defined functions. Finally, we briefly present applications of selected constrained peptides to illustrate their exceptional properties as drug candidates, molecular recognition probes, and minimalist catalysts.

Radiolabelled Peptides: Optimal Candidates for Theranostic Application in Oncology

“…[71] Small peptides can be evolved through the design of constrained peptides and foldamers to form complex structures that have high binding affinities and prolonged target engagement akin to large biologics, yet they exhibit favourable physiochemical characteristics akin to small molecules, affording ideal theranostics. [72,73] Samuel Gellman coined the term 'foldamer' to describe 'any polymer with a strong tendency to adopt a specific compact conformation' without the need for additional structural constraints such as cyclisation or stapling. [74,75] While constrained peptides can include any peptide with conformational constraints (including foldamers) it typically refers to monocyclic, bicyclic, or stapled peptides.…”

“…These conformations can be stabilised within constrained peptides and foldamers by careful restriction of the f and c torsion angles of the peptidic backbone. [72] Cyclisation is one useful method commonly employed to generate constrained peptides which mimic b-turn conformations, generally affording theranostics with higher binding affinity and metabolic stability. [78] Head-to-tail amide bond formation is one of the most common methods utilised to generate monocyclic peptides.…”

“…[95] Crosslinking of residues opposite to the binding face in an (i, i þ 3), (i, i þ 4), or (i, i þ 7) arrangement propagates a-helix formation by accommodating the required spatial configuration. [72] This crosslinking can be achieved through a variety of techniques, some typical examples include: the selective inclusion of reactive side-chain functional groups, [96,97] lactamisation, [98] or positioning cysteines in an (i, i þ 4) arrangement which can subsequently be cross-linked using a variety of linking groups such as a perfluoroaromatic scaffold (Fig. 12).…”

“…[102] Unfortunately, stapling remains very much underexplored for theranostics development, as most peptide-based theranostics currently available are derived from native-hormones or enzymatic substrates that do not adopt a-helical structures. [72,103] However, a-helical structures are one of the most abundant structural motifs responsible for PPIs and as such it is likely many emerging novel peptides targeting new proteins and enzymes will need to emulate these helical conformations for effective binding. [72,103] This leads to an enormous untapped potential for the development of next generation theranostics for oncology relevant biological targets.…”

“…[72,103] However, a-helical structures are one of the most abundant structural motifs responsible for PPIs and as such it is likely many emerging novel peptides targeting new proteins and enzymes will need to emulate these helical conformations for effective binding. [72,103] This leads to an enormous untapped potential for the development of next generation theranostics for oncology relevant biological targets.…”