Disulfide-bridged peptide macrobicycles from nature

Abstract

Disulfide-bridged peptide bicycles (DBPBs) are molecules that contain a transannular disulfide bridge within a macrocyclic framework. While DBPBs are precedented in nature, the development of synthetic analogues and their use as therapeutic agents has yet to realize their full potential. A series of naturally-occurring DBPBs and their respective structural and biological features is presented, followed by a description of synthetic methods used to prepare and understand these unique bicyclic systems. The synergy of high-throughput biology and synthetic chemistry should facilitate the development of novel DBPBs in the near future.

Broad Analysis of Vicinal Disulfides: Occurrences, Conformations with Cis or with Trans Peptides, and Functional Roles Including Sugar Binding

“…The only protein-structure survey we can find about vicinal disulfides 16 was early enough to identify just 9 distinct examples, all then thought to be trans; it categorizes the two different trans backbone conformations as types of β turns. However, computational and NMR work on small-molecule and short-peptide vicinal SS structures describes both cis and trans forms 19-21 , and high-resolution protein examples of both types have slowly accumulated. We feel, therefore, that an updated survey and analysis of both cis and trans vicinal disulfides seems useful and timely.…”

Bridged bicyclic peptides: Structure and function

“…The triple cross‐linked peptide dimer motif ( 3 ) has many different topological subsets, and is nearly always encountered as a multiply disulfide‐linked system (e.g., insulin family peptides, conotoxins). Such peptides will not be covered in this review: the topology of such peptides are interconvertible, some of which are not bridged bicycles, and further these systems have been extensively reviewed elsewhere …”

“…As described in the introduction, multiply cystine‐linked bicyclic peptides will not be covered in this review as these systems can be topologically unstable and have been extensively reviewed elsewhere . Nevertheless, modified cross‐links have been developed to solve the issue of disulfide scrambling in such peptides.…”

“…HIF1α is a transcription factor that controls expression of genes related to tumor progression and metastasis . Echinomycin 40 contains a thioether (thioacetal) bridge between Cys and S‐ methyl‐Cys residues (Figure ), and is a member of the quinoxaline family of bisintercalator antibiotics that also includes the disulfide‐linked bicyclic peptides triostin A and thiocoraline …”

Sulfur-Switch Ugi Reaction for Macrocyclic Disulfide-Bridged Peptidomimetics

“…19 Surprisingly, however, the isocyanide derived from enantiopure cysteine and its utility remains largely unexplored. 20 Hence, we herein describe the synthesis of the chiral cysteine isocyanide and its application in the Ugi MCR followed by oxidative cyclization to deliver disulfide-bridged cyclic peptidomimetics.…”