Abstract
Macrocyclic peptides are predominantly peptide structures bearing one or more rings and spanning multiple amino acid residues. Macrocyclization has become a common approach for improving the pharmacological properties and bioactivity of peptides. A variety of ribosomal-derived and non-ribosomal synthesized cyclization approaches have been established. The biosynthesis of backbone macrocyclic peptides using seven new emerging methodologies will be discussed with regard to the features and strengths of each platform rather than medicinal chemistry tools. The mRNA display variant, known as the random nonstandard peptide integrated discovery (RaPID) platform, utilizes flexible in vitro translation (FIT) to access macrocyclic peptides containing nonproteinogenic amino acids (NAAs). As a new discovery approach, the ribosomally synthesized and post-translationally modified peptides (RiPPs) method involves the combination of ribosomal synthesis and the phage screening platform together with macrocyclization chemistries to generate libraries of macrocyclic peptides. Meanwhile, the split-intein circular ligation of peptides and proteins (SICLOPPS) approach relies on the in vivo production of macrocyclic peptides. In vitro and in vivo peptide library screening is discussed as an advanced strategy for cyclic peptide selection. Specifically, biosynthetic bicyclic peptides are highlighted as versatile and attractive modalities. Bicyclic peptides represent another type of promising therapeutics that allow for building blocks with a heterotrimeric conjugate to address intractable challenges and enable multimer complexes via linkers. Additionally, we discuss the cell-free chemoenzymatic synthesis of macrocyclic peptides with a non-ribosomal catalase known as the non-ribosomal synthetase (NRPS) and chemo-enzymatic approach, with recombinant thioesterase (TE) domains. Novel insights into the use of peptide library tools, activity-based two-hybrid screening, structure diversification, inclusion of NAAs, combinatorial libraries, expanding the toolbox for macrocyclic peptides, bicyclic peptides, chemoenzymatic strategies, and future perspectives are presented. This review highlights the broad spectrum of strategy classes, novel platforms, structure diversity, chemical space, and functionalities of macrocyclic peptides enabled by emerging biosynthetic platforms to achieve bioactivity and for therapeutic purposes.
Highlights
Macrocyclic peptides, including monocyclic and bicyclic peptides, are privileged molecular modalities which can be used for diagnosis, disease treatment, and drug delivery [1,2]
Another highly synthetic approach reported by Nawatha et al integrated both the chemical synthesis of proteins and screening against trillion-member macrocyclic peptide libraries using random nonstandard peptide integrated discovery (RaPID), making post-translationally modified targets accessible for drug discovery [27]
An isolated TE demonstrated the capability of catalyzing the cyclization of linear peptides via a phosphopantetheine linker and building a cyclic peptide library derived from the antibiotic tyrocidine [14,15,75]
Summary
Macrocyclic peptides, including monocyclic and bicyclic peptides, are privileged molecular modalities which can be used for diagnosis (e.g., biosensors, glucose sensors), disease treatment (e.g., antimicrobial, cancer therapy), and drug delivery [1,2]. The main feature of RaPID is the generation of huge, trillion-member libraries of DNA-tagged cyclic peptides [27] The use of these libraries for target engagement, followed by DNA sequencing, enables selection of highly specific, tight-binding cyclic peptide sequences [27,42]. This work demonstrated the potential of the RaPID system for the discovery of a novel class of nonstandard peptides against previously non-druggable targets [25] Another highly synthetic approach reported by Nawatha et al integrated both the chemical synthesis of proteins and screening against trillion-member macrocyclic peptide libraries using RaPID, making post-translationally modified targets accessible for drug discovery [27]. Compared with other discovery platforms, limitations include the constraint of the tolerance of its host cell, challenges in system modifications and evolution, and limited accessibility of a single type of cyclic peptide topology [65]
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