1,4-Disubstituted-[1,2,3]triazolyl-Containing Analogues of MT-II: Design, Synthesis, Conformational Analysis, and Biological Activity

Abstract

Side chain-to-side chain cyclizations represent a strategy to select a family of bioactive conformations by reducing the entropy and enhancing the stabilization of functional ligand-induced receptor conformations. This structural manipulation contributes to increased target specificity, enhanced biological potency, improved pharmacokinetic properties, increased functional potency, and lowered metabolic susceptibility. The CuI-catalyzed azide–alkyne 1,3-dipolar Huisgen’s cycloaddition, the prototypic click reaction, presents a promising opportunity to develop a new paradigm for an orthogonal bioorganic and intramolecular side chain-to-side chain cyclization. In fact, the proteolytic stable 1,4- or 4,1-disubstituted [1,2,3]triazolyl moiety is isosteric with the peptide bond and can function as a surrogate of the classical side chain-to-side chain lactam forming bridge. Herein we report the design, synthesis, conformational analysis, and functional biological activity of a series of i-to-i+5 1,4- and 4,1-disubstituted [1,2,3]triazole-bridged cyclopeptides derived from MT-II, the homodetic Asp5 to Lys10 side chain-to-side chain bridged heptapeptide, an extensively studied agonist of melanocortin receptors.

Antibody Recognition in multiple sclerosis and rett syndrome using a collection of linear and cyclic N‐glucosylated antigenic probes

“…14 Therefore a relevant challenge to increase specificity and affinity in antibody recognition is to fine-tune peptides mimicking linear and/or conformational epitopes. 17,18 Recently, we confirmed by NMR-based conformational studies that the Glaser oxidative coupling can be considered as a "click" reaction stabilizing b-turn structures. The "click chemistry" leading to the triazole ring as lactam bridge mimic is one of the most fashion strategy employed to stabilize by cyclization helical, bturn, and/or b-hairpin structures.…”

“…The peptide was cleaved from the resin as described in the general protocol. Deprotection of the hydroxyl functions of sugar was accomplished in-solution as described in the general protocol ( H 2 N-O2Oc-Pra-Arg-Arg-Asn(Glc)-Gly-His-Thr-Pra-NH 2 (18). Ac-c[NPra-Arg-Asn(Glc)-Gly-His-NPra]-NH 2 (5).…”

“…The glycopeptides CSF114 (Glc) and H 2 N-O2Oc-Pra-RRN(Glc)GHT-Pra-NH 2 (18) were individually immobilized on functionalized carboxylated dex-tran matrix gold sensor chips. The glycopeptides CSF114 (Glc) and H 2 N-O2Oc-Pra-RRN(Glc)GHT-Pra-NH 2 (18) were individually immobilized on functionalized carboxylated dex-tran matrix gold sensor chips.…”

“…The resulting peptides C 11 H 23 CO-O2Oc-Pra-RRN(Glc)GHT-Pra-NH 2 , (16), C 13 H 27 CO-O2Oc-Pra-RRN(Glc)GHT-Pra-NH 2 (17), and H 2 N-O2Oc-Pra-RRN(Glc)GHT-Pra-NH 2 (18) were also tested in inhibition experiments to confirm that the introduced modification at the N-terminus did not hinder the antibody binding site ( Figure 1D). The resulting peptides C 11 H 23 CO-O2Oc-Pra-RRN(Glc)GHT-Pra-NH 2 , (16), C 13 H 27 CO-O2Oc-Pra-RRN(Glc)GHT-Pra-NH 2 (17), and H 2 N-O2Oc-Pra-RRN(Glc)GHT-Pra-NH 2 (18) were also tested in inhibition experiments to confirm that the introduced modification at the N-terminus did not hinder the antibody binding site ( Figure 1D).…”

Design, synthesis, and conformational studies of [DOTA]‐Octreotide analogs containing [1,2,3]triazolyl as a disulfide mimetic

“…We previously employed the Cu(I)‐catalyzed azide‐alkyne Huisgen's cycloaddition (CuAAC) to develop a convenient, facile, and versatile access to 1,4‐ or 4,1‐[1,2,3]triazolyl‐containing cyclic peptidomimetics and demonstrated their capacity to stabilize secondary structures such us α‐helix and β‐turns . The attractive disulfide and peptide bond mimetic capacities presented by the 1,4‐ or 4,1‐disubstituted [1,2,3]triazolyl moiety endows enhanced metabolic and chemical stability as compared to the disulfide function.…”