Bicyclic Peptides as Next‐Generation Therapeutics

Rhodes, Curran A.; Pei, Dehua

doi:10.1002/chem.201702117

Cited by 133 publications

(124 citation statements)

References 81 publications

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“…These data should be valuable for the rational design of more highly selective peptides that emulate the specificity of the anti‐IL‐17A and anti‐IL‐17F mAbs. Elimination or replacement of amino acids that are less critical for IL‐17F binding, backbone modification, incorporation of non‐natural amino acids, and increasing the conformational rigidity are strategies that we anticipate may further improve the binding characteristics of the developed ligands. Such approaches may facilitate the exploration of these ligands as novel alternatives to antibodies in various settings.…”

Section: Discussionmentioning

confidence: 99%

Epitope‐Targeted Macrocyclic Peptide Ligand with Picomolar Cooperative Binding to Interleukin‐17F

Lai¹,

Wilson²,

Loredo³

et al. 2018

Chemistry A European J

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The IL-17 cytokine family is associated with multiple immune and autoimmune diseases and comprises important diagnostic and therapeutic targets. This work reports the development of epitope-targeted ligands designed for differential detection of human IL-17F and its closest homologue IL-17A. Non-overlapping and unique epitopes on IL-17F and IL-17A were identified by comparative sequence analysis of the two proteins. Synthetic variants of these epitopes were utilized as targets for in situ click screens against a comprehensive library of synthetic peptide macrocycles with 5-mer variable regions. Single generation screens yielded selective binders for IL-17F and IL-17A with low cross-reactivity. Macrocyclic peptide binders against two distinct IL-17F epitopes were coupled using variable length chemical linkers to explore the physical chemistry of cooperative binding. The optimized linker length yielded a picomolar affinity binder, while retaining high selectivity. The presented method provides a rational approach towards targeting discontinuous epitopes, similar to what is naturally achieved by many B cell receptors.

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Section: Discussionmentioning

confidence: 99%

Epitope‐Targeted Macrocyclic Peptide Ligand with Picomolar Cooperative Binding to Interleukin‐17F

Lai¹,

Wilson²,

Loredo³

et al. 2018

Chemistry A European J

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“…Further, cyclic peptides have found applications as molecular imaging agents, biological probes and in materials chemistry . Bicyclic peptides offer additional advatages over monocyclic peptides, with increased conformational rigidity further improving their target binding affinity and selectivity, metabolic stability and membrane permeability . Bridged bicyclic peptides can be formed with a variety of structural motifs: The simplest motif is a head‐to‐tail cyclized macrocyclic peptide that is further constrained by an intramolecular linkage connecting two side chains of the peptide ( 1 , Figure ).…”

Section: Introductionmentioning

confidence: 99%

Bridged bicyclic peptides: Structure and function

Thombare

Hutton

2018

Peptide Science

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Bicyclic peptides are conformationally rigid molecules that can bind with high affinity and specificity to their protein target, yet are significantly more protease stable than their linear or monocyclic counterparts. This emerging class of peptides has great potential for the development of novel peptide therapeutics and molecular probes. In this review, we highlight the structural complexity, synthesis/biosynthesis, and biological applications of bridged bicyclic peptides.

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“…In this regard, peptide ligands mimicing the interacting motif with the conserved key interacting residues show potentials to target these intracellular targets. Peptides constraint with suitable methods were shown to have improved biophysical properties, including enhanced protease resistance, cell‐penetration, and/or target binding affinity . Many chemical methods have been developed to constrain peptides into helical conformation by attaching different tethers to the peptide side chains, including disulfide/thioether bond formation, ring‐closing metathesis, lactam ring formation, “click” chemistry, addition of perfluoroarenes, vinyl‐sulfide formation, and so on.…”

Section: Introductionmentioning

confidence: 99%

Effects of chiral center on an all‐hydrocarbon tethered peptide

Shi

Geng

et al. 2018

Peptide Science

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Recently, our group reported that a precisely positioned chiral center on a thioether tether could dominate the backbone peptides' secondary structures and modulate the peptides' biophysical properties. Helical peptides constructed with this chirality induced helicity (CIH) method were named as CIH peptide. In this work, we examined the effects of substituting the thioether tether with an all hydrocarbon tether for the biophysical property differences. Two peptide epimers were prepared and showed distinct secondary structures and the R epimer is helical. Comparing with its thioether counterpart, the all‐hydrocarbon R epimer showed slightly higher helical content, modest improved binding affinity with mammal double minute 2 (MDM2), while similar cell permeability and slightly higher membrane toxicity.

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Bicyclic Peptides as Next‐Generation Therapeutics

Cited by 133 publications

References 81 publications

Epitope‐Targeted Macrocyclic Peptide Ligand with Picomolar Cooperative Binding to Interleukin‐17F

Epitope‐Targeted Macrocyclic Peptide Ligand with Picomolar Cooperative Binding to Interleukin‐17F

Bridged bicyclic peptides: Structure and function

Effects of chiral center on an all‐hydrocarbon tethered peptide

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