Cyclic Peptides

Adusumalli, Srinivasa Rao; Yudin, Andrei K.; Rai, Vishal

doi:10.1002/9783527666911.ch8

Cited by 7 publications

(5 citation statements)

References 272 publications

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“…The interest in macrocyclic peptides and peptidomimetics has increased considerably with the identification of numerous natural cyclic peptides with a wide range of biological activities . One such compound, apicidin, displays inhibitory activity against histone deacetylase (HDAC) enzymes, which are validated as targets for anticancer chemotherapy .…”

Section: β-Peptoid Residues In Hybrid Backbonesmentioning

confidence: 99%

β-Peptoid Foldamers at Last

2015

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For a long time, peptides were considered unsuitable for drug development due to their inherently poor pharmacokinetic properties and proteolytic susceptibility. However, this paradigm has changed significantly in the past decade with the approval of numerous antibodies and proteins as drugs. In parallel, research in the field of synthetic molecules that are able to mimic or complement folding patterns exhibited by biopolymers, but are not recognized by proteases, have received considerable attention as well. Such entities were coined "foldamers" by Professor Gellman in an Account published in this journal in the late 1990s. Oligomers of N-alkylated 3-aminopropionic acid residues have been called β-peptoids due to their structural similarity to β-peptides and peptoids (N-alkylglycines), respectively. Because bona fide foldamer behavior has been demonstrated for both parent architectures, we wondered if the β-peptoids could serve as a successful addition to the known ensemble of peptidomimetic foldamers. When we entered this field, only the seminal description of libraries of β-peptoid dimers and trimers by Hamper et al. had been published a number of years earlier [ J. Org. Chem. 1998 , 63 , 708 ]. Perhaps somewhat naïvely in retrospect, we envisioned that elongation of chain length combined with introduction of bulky α-chiral side chains would deliver folded structures as reported for the α-peptoid counterparts. Initially, we, and others, were unsucessful in obtaining stable secondary structures of β-peptoid oligomers, and instead, these residues were either incorporated in cyclic structures or in combination with other types of residues to give peptidomimetic constructs with heterogeneous backbones. Amphiphilic architectures with various membrane-targeting activities, such as mimics of antimicrobial peptides or cell-penetrating peptides, have thus been particularly successful. Introduction of β-peptoid residues in histone deacetylase inhibitors mimicking nonribosomal cyclotetrapeptides have also been reported. In the present Account, we will sketch the scientific journey that ultimately delivered robustly folded β-peptoid oligomers. Contributions involving biological evaluation of peptidomimetic constructs containing β-peptoid residues, as mentioned above, which were investigated leading up to these recently reported high-resolution helical structures, will thus be discussed. On the basis of the work described in this Account, we envision that β-peptoids will find future utility as peptidomimetics for biomedical investigation containing both heterogeneous and homogeneous backbones. The recent demonstration of control over the secondary structure of a homogeneous β-peptoid backbone now enables structure-based design of scaffolds with predictable display of desired functionalities in three dimensions.

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Section: β-Peptoid Residues In Hybrid Backbonesmentioning

confidence: 99%

β-Peptoid Foldamers at Last

2015

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“…There is a great deal of evidence to indicate that Nature uses cyclization in bacteria, fungi, plants, and animals to constrain peptides into conformations that can selectively bind proteins and exert functions. − ,− Numerous peptides are cyclized through one or more disulfide bonds, such as the many peptide hormones including GPCR agonists (endothelin, oxytocin, orexin-A, urotensin-II, vasopressin, somatostatin, melanin-concentrating hormone, relaxin 2, sarafotoxin, calcitonin, etc. ), and there is evidence that they stabilize one or more turn conformations that mediate interaction with a GPCR. , However, not only disulfide bonds have been used for cyclizationthere are numerous ways in which Nature has achieved cyclization in peptides, indeed virtually every part of an amino acid has been adapted and modified as a cyclization point to create mono- and multicyclic peptides. − ,− …”

Section: Introductionmentioning

confidence: 99%

Crystal Structures of Protein-Bound Cyclic Peptides

et al. 2019

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Cyclization is an important post-translational modification of peptides and proteins that confers key advantages such as protection from proteolytic degradation, altered solubility, membrane permeability, bioavailability, and especially restricted conformational freedom in water that allows the peptide backbone to adopt the major secondary structure elements found in proteins. Non-ribosomal synthesis in bacteria, fungi, and plants or synthetic chemistry can introduce unnatural amino acids and non-peptidic constraints that modify peptide backbones and side chains to fine-tune cyclic peptide structure. Structures can be potentially altered further upon binding to a protein in biological environments. Here we analyze three-dimensional crystal structures for 211 bioactive cyclic peptides bound to 65 different proteins. The protein-bound cyclic peptides were examined for similarities and differences in bonding modes, for main-chain and side-chain structure, and for the importance of polarity, hydrogen bonds, hydrophobic effects, and water molecules in interactions with proteins. Many protein-bound cyclic peptides show backbone structures like those (strands, sheets, turns, helices, loops, or distorted variations) found at protein−protein binding interfaces. However, the notion of macrocycles simply as privileged scaffolds that primarily project side-chain substituents for complementary interactions with proteins is dispelled here. Unlike small-molecule drugs, the cyclic peptides do not rely mainly upon hydrophobic and van der Waals interactions for protein binding; they also use their main chain and side chains to form polar contacts and hydrogen bonds with proteins. Compared to small-molecule ligands, cyclic peptides can bind across larger, polar, and water-exposed protein surface areas, making many more contacts that can increase affinity, selectivity, biological activity, and ligand−receptor residence time. Cyclic peptides have a greater capacity than small-molecule drugs to modulate protein−protein interfaces that involve large, shallow, dynamic, polar, and water-exposed protein surfaces.

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“…Although Pci is a structural analogue of maleimide, the Pci-transfer is more functionally aligned with an emerging class of alternative amine-targeting methods and reagents, 105 including the 6 π -azaelectrocyclization reagents, [106][107][108][109][110] squarimides, [111][112][113] iminoboronates, 114 TAK-242 derivatives, 115,116 diazonium terephthalate esters, 117 twocomponent formaldehyde/indole couplings, 118 phthalaldehydes, 119 acylfluorides, 120 palladium-catalyzed arylations, 121 sulfonyl acrylates, 122,123 fluorophenyl esters, 85 DSHmediated acylations, 124 heteroaryl methylsulfones, 125 dinitroimidazoles, 126 and linchpindirected modification strategies. 127,128 The Pci-transfer reagents 18 and 27 were used in unusually high concentrations in the present study, compared with typical concentration ranges employed in bioconjugate chemistry. However, these are only the first generation of these reagents.…”

Section: Resultsmentioning

confidence: 99%

Pyrocinchonimides Conjugate to Amine Groups on Proteins via Imide Transfer

et al. 2020

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Advances in bioconjugation, the ability to link biomolecules to each other, small molecules, surfaces, and more, can spur the development of advanced materials and therapeutics. We have discovered that pyrocinchonimide, the dimethylated analog of maleimide, undergoes a surprising transformation with biomolecules. The reaction targets amines and involves an imide transfer, which has not been previously reported for bioconjugation purposes. Despite their similarity to maleimides, pyrocinchonimides do not react with free thiols. Though both lysine residues and the N-termini of proteins can receive the transferred imide, the reaction also exhibits a marked preference for certain amines that cannot solely be ascribed to solvent accessibility. This property is peculiar among amine-targeting reactions and can reduce combinatorial diversity when many available reactive amines are available, such as in the formation of antibody-drug conjugates. Unlike amides, the modification undergoes very slow reversion under high pH conditions. The reaction offers a thermodynamically controlled route to single or multiple modifications of proteins for a wide range of applications.

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Cyclic Peptides

Cited by 7 publications

References 272 publications

β-Peptoid Foldamers at Last

β-Peptoid Foldamers at Last

Crystal Structures of Protein-Bound Cyclic Peptides

Pyrocinchonimides Conjugate to Amine Groups on Proteins via Imide Transfer

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