title: 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 Cu(I)-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 Asp(5) to Lys(10) side chain-to-side chain bridged heptapeptide, an extensively studied agonist of melanocortin receptors.
authors.affiliation: Laboratoire SOSCO & PeptLab@UCP, EA4505, University of Cergy-Pontoise , 5 mail Gay-Lussac, Neuville sur Oise, F-95031 Cergy-Pontoise Cedex, France.
authors.forename: Chiara
authors.initials: C
authors.lastname: Testa
authors.forename: Mario
authors.initials: M
authors.lastname: Scrima
authors.forename: Manuela
authors.initials: M
authors.lastname: Grimaldi
authors.forename: Anna M
authors.initials: AM
authors.lastname: D'Ursi
authors.forename: Marvin L
authors.initials: ML
authors.lastname: Dirain
authors.forename: Nadège
authors.initials: N
authors.lastname: Lubin-Germain
authors.forename: Anamika
authors.initials: A
authors.lastname: Singh
authors.forename: Carrie
authors.initials: C
authors.lastname: Haskell-Luevano
authors.forename: Michael
authors.initials: M
authors.lastname: Chorev
authors.forename: Paolo
authors.initials: P
authors.lastname: Rovero
authors.forename: Anna M
authors.initials: AM
authors.lastname: Papini
mesh_terms: D001386:Azides / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003300:Copper / Q000737:chemistry; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D007769:Lactams / Q000737:chemistry*; D008024:Ligands; D016014:Linear Models; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008668:Metallothionein / Q000737:chemistry*; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry; D044101:Receptors, Melanocortin / Q000819:agonists; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
chemical_list: D001386:Azides; D007769:Lactams; D008024:Ligands; D010455:Peptides; D044101:Receptors, Melanocortin; D014230:Triazoles; D003300:Copper; D008668:Metallothionein