Abstract
Macrocyclic peptides are an emerging class of bioactive compounds for therapeutic use. In part, this is because they are capable of high potency and excellent target affinity and selectivity. Over the last decade, several biochemical techniques have been developed for the identification of bioactive macrocyclic peptides, allowing for the rapid isolation of high affinity ligands to a target of interest. A common feature of these techniques is a general reliance on thioether formation to effect macrocyclization. Increasingly, the compounds identified using these approaches have been subjected to x-ray crystallographic analysis bound to their respective targets, providing detailed structural information about their conformation and mechanism of target binding. The present review provides an overview of the target bound thioether-closed macrocyclic peptide structures that have been obtained to date.
Highlights
Macrocyclic peptides are an appealing chemical class for drug discovery
The structural constraints imbued by their macrocyclic structure provide both an improved target affinity and biological stability relative to their linear counterparts, and many bioactive macrocyclic peptides’ natural products are known
This study found that to be reported was the structure of the bicyclic peptide urokinase-type plasminogen activator (uPa)–UK18 in complex with uPa [1]
Summary
Macrocyclic peptides are an appealing chemical class for drug discovery. The structural constraints imbued by their macrocyclic structure provide both an improved target affinity and biological stability relative to their linear counterparts, and many bioactive macrocyclic peptides’ natural products are known. While the technical detail of these approaches has been reviewed in detail recently elsewhere, a brief description is warranted here Such techniques rely on biochemical peptide synthesis (i.e., ribosomal translation) to produce partially randomized peptide libraries that are cyclized post-translationally, either enzymatically or through non-enzymatic chemical reactions, to yield macrocyclic libraries, which can be screened for target affinity. While these techniques employ diverse methodologies, all of them involve the co-localization of each peptide macrocycle and a cognate encoding nucleic acid.
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