Catalytic Peptides: the Challenge between Simplicity and Functionality

Abstract

Enzymes' machinery has been an inspiration for chemists. Peptides are vital players in the origin of life, being ancestors of complex enzymes. Even short peptides that are simple in terms of the number of residues are reprogrammable and built to encode chemical information for catalysis, substrate recognition, and molecular interactions. The combinatorial search of the sequence space led to identifying peptides with catalytic activities. However, most of these sequences remain unevolved, leading to modest rates in aqueous media. Short peptides present conformational flexibility, which is their primary liability for catalysis. To overcome this, supramolecular motifs and secondary frameworks are used as scaffolds to incorporate catalytic residues and improve their efficiency. This review discusses the strategies used to discover and evolve catalytic function in short peptides beyond the de novo design and the advantages of using these approaches to enhance catalysis.

Factors influencing the catalytic activity of metal-dependent histidine-rich peptides: sequence, conformation, stereochemistry, self-assembly or their interplay?

“…22,23 By organizing peptides into specific architectures, it is possible to create catalytic sites with enhanced activity and selectivity. 20,21,24 In addition, peptides are susceptible to proteolytic degradation, have reduced stability in plasma, and limited oral bioavailability. 18 Nevertheless, recent advances in peptide synthesis and modification techniques have helped overcome some of these limitations.…”

“…29 Several design strategies have been developed to identify effective catalytic peptides, including mimicking natural enzymes, incorporating catalytic motifs or cofactors, and using directed evolution or combinatorial chemistry. 21,30,31 The most prominent strategies to mimic natural enzymes include metal coordination and incorporation of catalytic triad residues into short peptide sequences with selfassembly propensity. 32 The coordination of metal ions within peptides is often accomplished through specific amino acid residues, such as histidine, cysteine, aspartic acid, and glutamic acid, that can act as ligands for metal ions and consequently stabilize them within the peptide structure.…”

“…18,19 Compared to enzymes, catalytic peptides offer several advantages, such as their smaller size, simpler structures, modularity, and ease of production. 20,21 Using peptides as catalysts may enable access to a chemical space larger than that of traditional small-molecule catalysts, leading to new possibilities for synthetic chemistry and biotechnology.…”

Short Peptides for Hydrolase Supramolecular Mimicry and Their Potential Applications

“…In particular, in the case of enzymatic mimicry, it can be advantageous to exploit peptides’ supramolecular organization through self-assembly so as to recreate hydrophobic pockets where reagents are confined and protected from the bulk solvent for catalysis to occur [ 21 ]. Mastering this process is highly attractive given the possibility of positioning different functionalities designed ad hoc [ 22 , 23 ] thanks to the great molecular diversity of peptides and the easy and modular solid-phase synthesis. Finally, if enzymatic activity arises with supramolecular organization, in line of principle, it should be possible to design biocatalysts that can be switched on/off with assembly/disassembly cycles, and that can even work in tandem to mimic the natural modes of biochemical cascades [ 24 ].…”

A Simple Screening and Optimization Bioprocess for Long-Chain Peptide Catalysts Applied to Asymmetric Aldol Reaction

“…While long-chain peptides are highly modular, structurally diverse, and easily accessible from nature's chiral pool [30,31], they are simpler in structure compared to enzymes and possess the atom economy of organic small molecules [32]. So, they should have been an attractive candidate for discovering or designing new green catalysts [33][34][35]. However, long-chain peptide catalysts were deemed unnecessary to synthesize based on a comparison between tripeptides and tetrapeptides.…”