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제124회 대한화학회 학술발표회, 총회 및 기기전시회 안내 Strategies for modulation of secondary structures to optimise biological recognition

2019년 8월 29일 13시 59분 04초
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목 16시 : 20분
Life Chemistry - [Life Chemistry Division-Korean Peptide Protein Society Joint Symposium] Recent Trends in Peptide Chemistry
저자 및
Anna Maria Papini
Chemistry, University of Florence, Italy
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승인 1건
Side chain-to-side chain cyclizations represent a strategy for enrichment of bioactive conformational ensembles. Structural rigidification reduces entropy and may lock molecules into receptor binding conformations. Anyway, structural manipulations contribute to enhance target specificity, induce higher binding affinity and biological potency, and lead very often to lower metabolic susceptibility and more favorable pharmacokinetics. The CuI-catalyzed azide−alkyne 1,3-dipolar Huisgen’s cycloaddition (CuAAC) provides a convenient and versatile access to cyclic peptidomimetics following incorporation of the building blocks Nα-Fmoc-Xaa(ω-N3)-OH and Nα-Fmoc-Yaa(ω-yl)-OH. The proteolytic stable side chain-to-side chain bridging [1,2,3]triazolyl moiety in peptides, is isosteric with the peptide bond and can function as a surrogate of the classical lactam forming bridge. As a proof-of-concept we introduced the [1,2,3]triazolyl bridge in a PTHrP model cyclopeptide demonstrating that i-to-i+4 side chain-to-side chain cyclization offers a powerful approach for generating stable helix mimetic structures. Then we demonstrated that i-to-i+5 side chain-to-side chain 1,4-disubstituted [1,2,3]triazolyl-bridge can stabilize β-turn conformations in MT-II peptides. Not only the [1,2,3]-triazolyl moiety but also bridge size and its location and orientation within the bridge appear to be fundamental to mimic the biological activity. In fact, conformational and biological studies confirmed that [1,2,3]triazolyl-mediated side chain-to-side chain cyclization results in conformational stabilization of type-I β turn generating heterodetic cyclopeptides with enhanced in vitro potency and improved receptor subtype selectivity. The same approach has been also successfully used to replace the susceptible disulfide bridge stabilizing the bioactive conformational behavior of Octreotide-derived radiotherapeutics. On the other hand we demonstrated that dicarba analogs in which the bulky aromatic side chain of Tyr(Bzl) favored the formation of a 310-helix, displayed enhanced sst5 selectivity suppressing the sst2 affinity. Efficient on resin MW-assisted RCM allowed to investigate the influence of the stereochemistry of some strategic amino acids on the propensity to give the cyclic compounds in mild conditions and new DOTA-conjugated Octreotide analogs exhibited nanomolar affinities on sst2 and sst5 somatostatin receptor subtypes. Stabilization of β-turn structures was also achieved by a 1,3-butadiyne constraint via the Glaser oxidative coupling to mimic conformational epitopes in the synthetic peptide CSF114(Glc) previously designed to fold as a type I’ β-turn structure recognising specific antibodies in multiple sclerosis and Rett Syndrome. Moreover, a synthetic photochromic azobenzene amino acid derivative was introduced as a turn element to replace the P-N-H fragment at positions 7-9 (involved in the β-hairpin in the peptide analogue [Pro7,Asn8,Thr10]CSF114 previously designed to fold as a type I β-turn optimized structure to recognize antibodies. The electronic properties of the novel azopeptidomimetic analog were investigated and we verified that isomerization results strongly favored by exciting into the ππ* transition. Moreover, conformational changes induced by the cis↔ trans azopeptidomimetic switch were investigated by NMR in different solvents.