Template-Constrained Somatostatin Analogues:  A Biphenyl Linker Induces a Type-V‘ Turn

Cheng, Richard P.; Suich, Daniel J.; Cheng, Hong; Röder, Heinrich; DeGrado, William F.

doi:10.1021/ja0116932

Cited by 19 publications

(19 citation statements)

References 20 publications

(26 reference statements)

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“…Degrado and coworkers (46), Boger and Myers (47), and others have shown the utility of such template-constrained cyclic peptides (48,49), and how polarity and geometry of the template can influence the shape and function of the peptide domain (50). Our laboratory has also explored templates for forming macrocyclic peptides (51)(52)(53).…”

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confidence: 94%

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

Lawson

Rose

Harran

2013

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

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Peptide-protein interactions are important mediators of cellularsignaling events. Consensus binding motifs (also known as short linear motifs) within these contacts underpin molecular recognition, yet have poor pharmacological properties as discrete species. Here, we present methods to transform intact peptides into stable, templated macrocycles. Two simple steps install the template. The key reaction is a palladium-catalyzed macrocyclization. The catalysis has broad scope and efficiently forms large rings by engaging native peptide functionality including phenols, imidazoles, amines, and carboxylic acids without the necessity of protecting groups. The tunable reactivity of the template gives the process special utility. Defined changes in reaction conditions markedly alter chemoselectivity. In all cases examined, cyclization occurs rapidly and in high yield at room temperature, regardless of peptide composition or chain length. We show that conformational restraints imparted by the template stabilize secondary structure and enhance proteolytic stability in vitro. Palladium-catalyzed internal cinnamylation is a strong complement to existing methods for peptide modification. S ynthetic peptides and peptidomimetics play wide-ranging roles in pharmacology and drug discovery. Interest in these substances continues to grow, particularly as medicinal chemistry pushes further into control of cellular-signaling events mediated by protein-protein interactions (PPIs) (1-3). The subset of socalled "druggable" PPIs includes those mediated by consensus peptides, where binding determinants are localized within defined motifs (4-8). Experimental data as well as computational/ bioinformatic efforts (9-11) to identify "short linear motifs" within signaling proteins suggest that the number of druggable PPIs has been underestimated (12, 13). Considerable opportunity exists for new chemistry in this area (14). Synthetic peptides that target "hot spots" on protein surfaces are a logical entry to drug-discovery programs (15-19). However, native peptides generally have poor pharmacological properties (20). Modifications that offset those limitations while stably recapitulating proteinbinding conformations are of considerable interest (14,(21)(22)(23).Ring-forming reactions are prominent among alterations found to improve the stability and performance of peptides (24-27). They find broad utility in synthesis and, increasingly, in combination with phage, ribosome, and mRNA display technologies (28-32). Relative to their acyclic counterparts, cyclic peptides have more defined conformations and are less prone to aggregate (33). Head-to-tail lactamization is the most common method to synthesize cyclic peptides (34-36). Internal disulfide bonding is also used (37, 38), as are newer techniques such as ring-closing olefin metathesis (39) and catalyzed cycloaddition of azides to alkynes (40-42). These procedures rely on judicious use of protecting groups and/or tailored amino acid residues (Fig. 1A) (43, 44). Careful attention must be paid to...

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confidence: 94%

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

Lawson

Rose

Harran

2013

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

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“…[9] Through observation of the packing of the secondary structural units in the solid state, tertiary structural motifs potentially available for b-peptides were identified; Xray crystallographic studies revealed a H14 helix-bundle motif [10] and a polar pleated sheet. [3] As a further step towards tertiary structures, designed b-peptide helices have been observed to exhibit self-association in solution, [11][12][13][14] but the creation of distinct tertiary structures with specific morphologies still remains a challenge.…”

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confidence: 99%

Secondary Structure Dependent Self‐Assembly of β‐Peptides into Nanosized Fibrils and Membranes

et al. 2006

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In control: The secondary structure dependent self‐assembly of β‐peptides in solution proves that natural biopolymers are not unique in their highly structured conformational behavior. Stereochemically controlled secondary structural units of β‐peptide strands and helices intrinsically self‐associate into pleated‐sheet sandwiches (see picture) and helix‐bundle membranes, respectively.

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“…[48] In jüngeren Ansätzen wurden ein Dicarba-Linker 42, Biphenylgerüste 43 oder die cyclische a-Aminosäure [1S,2S,5R]-2-Amino-3,5-dimethyl-2-cyclohex-3-encarbonsäure 44 anstelle von Prolin eingebaut. [51] Andere Kehrenmimetika für GPCRs als Zielproteine umfassen Agonisten (45-52) von Melanocortin, Bradykinin, Casmorphin, Endothelin, Enkephalin, GHRP-2, Gonadotropin-freisetzendes Hormon, Oxytocin und Vasopressin (Abbildung 9). [52][53][54][55][56][57] Nicht nur für GPCRs wurden verstrebte cyclische Peptide entwickelt, sondern auch, um die Kehren vieler anderer Proteine und Peptide nachzubilden.…”

Section: Cyclische Peptidkehrenunclassified

Fixierung cyclischer Peptide: Mimetika von Proteinstrukturmotiven

et al. 2014

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Viele Proteine entfalten ihre biologische Aktivität über kleine exponierte Oberflächenregionen aus gefalteten Peptiden mit wohldefinierten dreidimensionalen Strukturen, Epitope genannt. Kurze synthetische Peptidsequenzen, die diesen bioaktiven Proteinoberflächen entsprechen, bilden in Wasser keine thermodynamisch stabilen proteinähnlichen Strukturen. Die Bildung proteinähnlicher biologisch aktiver Konformationen (Stränge, Helices, Kehren) kann jedoch durch Cyclisierung in Verbindung mit anderen molekularen Verstrebungen induziert werden. Letztere helfen bei der Feinabstimmung der dreidimensionalen Struktur. Solche fixierten cyclischen Peptide können ähnliche biologische Aktivitäten und Wirkungen wie das als Vorbild dienende Protein haben, sodass sie als biologische Sonden und Leitstrukturen für Therapeutika, Diagnostika und Impfstoffe dienen können. Dieser Aufsatz beleuchtet Beispiele für cyclische Peptide, die dreidimensionale Strukturen von Strang‐, Kehren‐ oder Helixabschnitten von Peptiden und Proteinen nachahmen und beschreibt einige weitere Elemente, die in cyclisch peptidischen Naturstoffen und synthetischen makrocyclischen Peptidomimetika vorkommen, dort die Peptidstruktur verfeinern und ihr biologische Aktivitäten verleihen.

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Template-Constrained Somatostatin Analogues: A Biphenyl Linker Induces a Type-V‘ Turn

Cited by 19 publications

References 20 publications

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

Secondary Structure Dependent Self‐Assembly of β‐Peptides into Nanosized Fibrils and Membranes

Fixierung cyclischer Peptide: Mimetika von Proteinstrukturmotiven

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