Macrocyclization strategies for cyclic peptides and peptidomimetics

Bechtler, Clément; Lamers, Christina

doi:10.1039/d1md00083g

Cited by 126 publications

(88 citation statements)

References 354 publications

(588 reference statements)

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“…A plethora of chemistries have been developed for cyclization, ranging from natural disulfide bridges or isopeptide bonds to metal-catalyzed ring-closing metathesis (RCM), as well as azide-alkyne and Diels-Alder cycloadditions [26,27]. Moreover, peptide conformations may be further constrained by multicyclization and the use of chemical scaffolds to mediate linkage [28].…”

Section: Cyclizationmentioning

confidence: 99%

Protease-Resistant Peptides for Targeting and Intracellular Delivery of Therapeutics

et al. 2021

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Peptides show high promise in the targeting and intracellular delivery of next-generation bio- and nano-therapeutics. However, the proteolytic susceptibility of peptides is one of the major limitations of their activity in biological environments. Numerous strategies have been devised to chemically enhance the resistance of peptides to proteolysis, ranging from N- and C-termini protection to cyclization, and including backbone modification, incorporation of amino acids with non-canonical side chains and conjugation. Since conjugation of nanocarriers or other cargoes to peptides for targeting and cell penetration may already provide some degree of shielding, the question arises about the relevance of using protease-resistant sequences for these applications. Aiming to answer this question, here we provide a critical review on protease-resistant targeting peptides and cell-penetrating peptides (CPPs). Two main approaches have been used on these classes of peptides: enantio/retro-enantio isomerization and cyclization. On one hand, enantio/retro-enantio isomerization has been shown to provide a clear enhancement in peptide efficiency with respect to parent L-amino acid peptides, especially when applied to peptides for drug delivery to the brain. On the other hand, cyclization also clearly increases peptide transport capacity, although contribution from enhanced protease resistance or affinity is often not dissected. Overall, we conclude that although conjugation often offers some degree of protection to proteolysis in targeting peptides and CPPs, modification of peptide sequences to further enhance protease resistance can greatly increase homing and transport efficiency.

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Section: Cyclizationmentioning

confidence: 99%

Protease-Resistant Peptides for Targeting and Intracellular Delivery of Therapeutics

et al. 2021

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“… 36 − 42 To prevent proteolytic cleavage of specific amide bonds, site-directed engineering of the l -α-peptide backbone with unnatural amino acids (e.g., D-α, N α -alkylated, C α -substituted, β- and γ-amino acids) 43 − 47 and amide bond mimetics (e.g., thioamides, 48 azapeptides, 49 1,4-disubstituted 1,2,3-triazoles 50 ) has been developed. 51 More general strategies for molecular peptide stabilization involve polymer conjugation 52 , 53 and the use of cyclization to engineer rigid structures, 42 , 54 − 58 both of which can prevent hydrolysis by hindering protease access to cleavable bonds. N-to-C-terminal backbone cyclization and side-chain stapling via disulfide bonds are also key structural motifs in several natural peptide scaffolds that are proposed as stable templates to engineer drug leads via grafting small epitopes into their framework.…”

Section: Introductionmentioning

confidence: 99%

On the Utility of Chemical Strategies to Improve Peptide Gut Stability

et al. 2022

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Inherent susceptibility of peptides to enzymatic degradation in the gastrointestinal tract is a key bottleneck in oral peptide drug development. Here, we present a systematic analysis of (i) the gut stability of disulfide-rich peptide scaffolds, orally administered peptide therapeutics, and well-known neuropeptides and (ii) medicinal chemistry strategies to improve peptide gut stability. Among a broad range of studied peptides, cyclotides were the only scaffold class to resist gastrointestinal degradation, even when grafted with non-native sequences. Backbone cyclization, a frequently applied strategy, failed to improve stability in intestinal fluid, but several site-specific alterations proved efficient. This work furthermore highlights the importance of standardized gut stability test conditions and suggests defined protocols to facilitate cross-study comparison. Together, our results provide a comparative overview and framework for the chemical engineering of gut-stable peptides, which should be valuable for the development of orally administered peptide therapeutics and molecular probes targeting receptors within the gastrointestinal tract.

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“…The ability to potently interact with featureless surfaces has been demonstrated by the numerous successes of peptides as potent inhibitors of protein-protein interactions ( Pelay-Gimeno et al, 2015 ; Dougherty et al, 2017 ; Sawyer et al, 2017 ; Vinogradov et al, 2019 ; Wang X. et al, 2021 ). Cyclization of a peptide is often required for potent binding as is illustrated by the fact that the linear equivalents of these peptides typically bind with lower affinity due to their high flexibility and the therefore higher entropic penalty upon binding ( Pelay-Gimeno et al, 2015 ; Wang H. et al, 2021 ; Bechtler and Lamers, 2021 ). A challenge in the development of a potent cyclic peptide is the need to identify the right cyclization strategy as incorrect conformational restraints can lead to a peptide that is not able to bind its target efficiently ( Pelay-Gimeno et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

RNA-Binding Macrocyclic Peptides

Pal

Hart

2022

Front. Mol. Biosci.

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Being able to effectively target RNA with potent ligands will open up a large number of potential therapeutic options. The knowledge on how to achieve this is ever expanding but an important question that remains open is what chemical matter is suitable to achieve this goal. The high flexibility of an RNA as well as its more limited chemical diversity and featureless binding sites can be difficult to target selectively but can be addressed by well-designed cyclic peptides. In this review we will provide an overview of reported cyclic peptide ligands for therapeutically relevant RNA targets and discuss the methods used to discover them. We will also provide critical insights into the properties required for potent and selective interaction and suggestions on how to assess these parameters. The use of cyclic peptides to target RNA is still in its infancy but the lessons learned from past examples can be adopted for the development of novel potent and selective ligands.

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Macrocyclization strategies for cyclic peptides and peptidomimetics

Abstract: Macrocyclization between head, tail or sidechains is a frequently employed strategy to enhance peptide and peptidomimetic stability, selectivity and affinity.

Cited by 126 publications

References 354 publications

Protease-Resistant Peptides for Targeting and Intracellular Delivery of Therapeutics

Protease-Resistant Peptides for Targeting and Intracellular Delivery of Therapeutics

On the Utility of Chemical Strategies to Improve Peptide Gut Stability

RNA-Binding Macrocyclic Peptides

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