Selection-Based Discovery of Druglike Macrocyclic Peptides

Passioura, Toby; Katoh, Takayuki; Goto, Yuki; Suga, Hiroaki

doi:10.1146/annurev-biochem-060713-035456

Cited by 201 publications

(168 citation statements)

References 137 publications

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“…Similarly, a cDNA display library was cyclized [44] and a phage display library was bi-cyclized [45] through disulfide bonds formed in cysteine-rich peptides and used to select for peptide aptamers. Additional work on macrocyclic peptide selections has been recently reviewed [46]. …”

Section: Expanding the Scope Of Selections To New Propertiesmentioning

confidence: 99%

Advances in the directed evolution of proteins

Lane

Seelig

2014

Current Opinion in Chemical Biology

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Natural evolution has produced a great diversity of proteins that can be harnessed for numerous applications in biotechnology and pharmaceutical science. Commonly, specific applications require proteins to be tailored by protein engineering. Directed evolution is a type of protein engineering that yields proteins with the desired properties under well-defined conditions and in a practical time frame. While directed evolution has been employed for decades, recent creative developments enable the generation of proteins with previously inaccessible properties. Novel selection strategies, faster techniques, the inclusion of unnatural amino acids or modifications, and the symbiosis of rational design approaches and directed evolution continue to advance protein engineering.

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Section: Expanding the Scope Of Selections To New Propertiesmentioning

confidence: 99%

Advances in the directed evolution of proteins

Lane

Seelig

2014

Current Opinion in Chemical Biology

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“…RiPP | biosynthesis | peptide | plant | orbitide M acrocyclic peptides have become appealing targets for drug discovery efforts due to the emergence over the past decade of multiple routes for rapid synthesis and screening (1). The drug-like properties of cyclic peptides arise from their constrained rigid structure, improved bioavailability, membrane permeability relative to linear peptides, and resistance to degradation by host proteases (2)(3)(4).…”

mentioning

confidence: 99%

Characterization of the macrocyclase involved in the biosynthesis of RiPP cyclic peptides in plants

Chekan

Estrada

Covello

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Enzymes that can catalyze the macrocyclization of linear peptide substrates have long been sought for the production of libraries of structurally diverse scaffolds via combinatorial gene assembly as well as to afford rapid in vivo screening methods. Orbitides are plant ribosomally synthesized and posttranslationally modified peptides (RiPPs) of various sizes and topologies, several of which are shown to be biologically active. The diversity in size and sequence of orbitides suggests that the corresponding macrocyclases may be ideal catalysts for production of cyclic peptides. Here we present the biochemical characterization and crystal structures of the plant enzyme PCY1 involved in orbitide macrocyclization. These studies demonstrate how the PCY1 S9A protease fold has been adapted for transamidation, rather than hydrolysis, of acyl-enzyme intermediates to yield cyclic products. Notably, PCY1 uses an unusual strategy in which the cleaved C-terminal follower peptide from the substrate stabilizes the enzyme in a productive conformation to facilitate macrocyclization of the N-terminal fragment. The broad substrate tolerance of PCY1 can be exploited as a biotechnological tool to generate structurally diverse arrays of macrocycles, including those with nonproteinogenic elements.RiPP | biosynthesis | peptide | plant | orbitide

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“…Two selection methods have been used for in vitro discovery of tight binding non-reducible macrocyclic peptides, 8 with the difference being in the means of linking sequence information to the displayed peptide. These methods are phage and mRNA display.…”

Section: Selection Methodsmentioning

confidence: 99%

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

et al. 2015

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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.

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Selection-Based Discovery of Druglike Macrocyclic Peptides

Cited by 201 publications

References 137 publications

Advances in the directed evolution of proteins

Advances in the directed evolution of proteins

Characterization of the macrocyclase involved in the biosynthesis of RiPP cyclic peptides in plants

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

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