Synthesis of macrocyclic organo-peptide hybrids from ribosomal polypeptide precursors via CuAAC-/hydrazide-mediated cyclization.
Synthesis of macrocyclic organo-peptide hybrids from ribosomal polypeptide precursors via CuAAC-/hydrazide-mediated cyclization.
复制标题
通过 CuAAC-/酰肼介导的环化从核糖体多肽前体合成大环有机肽杂交体。
DOI：
10.1007/978-1-4939-2020-4_2
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Fasan,Rudi
中科院分区：
文献类型：
--
作者：
Smith,JessicaM;Fasan,Rudi
大环肽作为一种潜在的新的化学探针和治疗药物的来源越来越受到人们的关注。特别是，它们的构象限制结构与高度的功能和立体化学复杂性相结合，使它们成为具有高亲和力和选择性的靶向生物分子的有前途的支架。这种结构类别的探索依赖于用于产生大环肽基分子的大型和多样化文库的有效和通用方法的可用性。为此，我们已经开发了一种方法，用于通过核糖体衍生的多肽序列与非肽有机接头的环化来合成杂合有机肽大环化合物。该策略依赖于叠氮化物/酰肼基“合成前体”与内含肽融合多肽的化学选择性和生物正交连接，内含肽融合多肽具有侧链炔官能性。发现这种大环化方法在跨越4-12个残基的一系列不同靶肽序列以及多种基于单芳基和二芳基的合成前体中高效进行。这种多功能性与将非蛋白质支架整合到遗传编码的肽序列中的可能性相结合，使得这种方法对于基于肽的大环化合物的高度多样性文库的创建和筛选具有特别高的价值。
Macrocyclic peptides have attracted increasing attention as a potential new source of chemical probes and therapeutics. In particular, their conformationally restricted structure combined with a high degree of functional and stereochemical complexity makes them promising scaffolds for targeting biomolecules with high affinity and selectivity. The exploration of this structural class relies on the availability of efficient and versatile methods for the generation of large and diversified libraries of macrocyclic peptide-based molecules. To this end, we have developed a methodology for the synthesis of hybrid organo-peptide macrocycles via the cyclization of ribosomally derived polypeptide sequences with non-peptidic organic linkers. This strategy relies on the chemoselective and bioorthogonal ligation of azide/hydrazide-based “synthetic precursors” with intein-fused polypeptides harboring a side-chain alkyne functionality. This macrocyclization approach was found to proceed with high efficiency across a range of different target peptide sequences spanning 4–12 residues as well as across multiple mono- and diaryl-based synthetic precursors. This versatility combined with the possibility to integrate non-proteinogenic scaffolds into genetically encoded peptide sequences makes this methodology of particularly high value toward the creation and screening of highly diverse libraries of peptide-based macrocycles.