Peptide Macrocyclization Inspired by Non-Ribosomal Imine Natural Products

Abstract

A thermodynamic approach to peptide macrocyclization inspired by the cyclization of non-ribosomal peptide aldehydes is presented. The method provides access to structurally diverse macrocycles by exploiting the reactivity of transient macrocyclic peptide imines toward inter- and intramolecular nucleophiles. Reactions are performed in aqueous media, in the absence of side chain protecting groups, and are tolerant of all proteinogenic functional groups. Macrocyclic products bearing non-native and rigidifying structural motifs, isotopic labels, and a variety of bioorthogonal handles are prepared, along with analogues of four distinct natural products. Structural interrogation of the linear and macrocyclic peptides using variable-temperature NMR and circular dichroism suggests that preorganization of linear substrates is not a prerequisite for macrocyclization.

Residue-Specific Peptide Modification: A Chemist’s Guide

“…4–10 Alternative modifications at the N-terminus 111 often rely on participation from the associated side-chain functional group; reactions that engage ionizable residues (e.g., Cys) are common (entries 47 and 48), 83–85 as are examples that employ aromatic (entry 56) 94,95 and other nucleophilic side chains (e.g., Ser and Thr). 89 The formation of heterocycles is a common approach (entries 47–49, 51, 53, and 56) 83–86,89,91,94,95 as is N-terminal oxidation and further diversification (entries 50 and 51). 87–89 …”

Orally Active Peptides: Is There a Magic Bullet?

“…1,2,3triazoles, [143] thiazole, [112] or 1,3,4-oxadiazoles [144] and thus increases peptide rigidity iii)used for backbone cyclization, e.g. 1,2,3-triazoles, [145] 1,3,4-oxadiazoles, [144] thiazoles, [146] or thiazolidines [146b] iv) sanguinamid Aa nd danamide F(F= 51 AE 9%)d erived from it, are the most prominent examples [112] v) many reviews dealing with heterocycle-containing peptides have been recently published [142,147] [142, 144, 147b] cyclic alanine i) known as Freidinger lactam [148] in combination with R 1 = Leu, a b-turn mimetic in acyclic peptide ii)possesses the same trans-dominated equilibriumast he standard peptide bond in contrast with N-methylation or Pro iii)removal of hydrogen bond donor iv) increasess erum stability and cell permeability [149] v) its effect on bioavailability has not been systematicallys tudied [148,149] a-methylation i) a-methylation marginally increasesthe entire lipophilicity of peptides ii)rarely used [150] iii)present three times in ZYGO1 (20), alinear orally available GLP-1 antagonist [151] [150]…”

Peptide Macrocycles Developed from Precisely Regulated Multiple Cyclization of Unprotected Peptides

“…The overall rigidity of these peptide macrocycles is usually determined by the interplay of cyclic constraints and intramolecular hydrogen‐bonding networks. Indeed, there is increasing evidence to show the feasibility of stabilizing the structure of peptide macrocycles by rigidifying motifs at the ring junction or introducing hydrogen‐bond‐donating/‐accepting groups into the linkage . In addition, inspired by pioneering work by Craik and co‐workers, we argued that peptide macrocycles reminiscent of grafting loops in disulfide‐rich peptides might be further rigidified by the introduction of additional cyclizations.…”