Model foldamers: applications and structures of stable macrocyclic peptides identified using in vitro selection

Abstract

Foldamers are synthetic molecules that seek to mimic the structure-forming propensity of biomolecules, such as proteins. However, on a short oligomer scale, peptides often do not fold in the same manner as large proteins, despite being composed of the same amino acid building blocks. Constraints to available peptide conformations can improve these folding characteristics. One important constraint that leads to an increase in folding behaviour is the formation of a macrocycle, while doing this by means other than disulfide bond formation ensures that this structural constraint persists in all biological settings. Additional non-natural features, such as incorporation of amino acids with unusual side chains, D-amino acids, N-alkyl amino acids, and b-hydroxy acids, further mimic the synthetic characteristics of foldamers, giving a class of compounds that is intermediate between natural proteins and synthetic foldamers. In vitro selection methods, such as phage and mRNA display, allow access to de novo peptides based solely on their ability to bind a target, potentially giving access to unique structures and functions. Recently, a series of structures have become available for several such partially synthetic macrocyclic peptides derived from in vitro selection. Here we present an overview of the structural features of these stable macrocyclic peptides and their binding to protein targets, as well as some initial indications of their folding behaviour free in solution, and discuss implications for the future design and functions of foldamers.

Rapid Discovery of Potent and Selective Glycosidase-Inhibiting De Novo Peptides

“…The three-dimensional fold of piHA-Dm is unlike any other macrocyclic ligands discovered to date using peptide display technologies (Jongkees et al, 2015). A lariat-type peptide has previously been observed in a co-crystallization ligand for a MATE (Multidrug And Toxic compound Extrusion) transporter, but in that case the C-terminal tail was largely unstructured and there were fewer intramolecular interactions (Tanaka et al, 2013).…”

De novo macrocyclic peptides that specifically modulate Lys48-linked ubiquitin chains

“…However, this represents a significant challenge for molecular recognition, given the number of possible Ub chains 4 and the often subtle differences in their structure and dynamics 20,21 . Yet, we have envisioned that this could be achieved using macrocyclic peptides, which can tightly interact with proteins using extended interfaces 22 , similar to natural protein-protein interactions, but at the same time are small enough to emulate druglike in vivo properties of small molecules 23 .…”

Towards Tuneable Retaining Glycosidase‐Inhibiting Peptides by Mimicry of a Plant Flavonol Warhead

“…Such a drop in activity is not uncommon for macrocyclic peptide ligands from in vitro selection upon conversion into their linear analogues . This is typically attributed to preorganisation of the ligand in the binding conformation, which reduces the entropic cost of binding, but very few solution structures of macrocyclic peptides from in vitro selection have been reported to support this . To investigate whether the 3 10 ‐helical conformation seen in our previously reported crystal structure of piHA‐Dm was also present if the peptide was free in solution, we probed its folding behaviour by using circular dichroism (CD; Figure ).…”