Medicinal Chemistry and Chemical Biology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
Chembiochem. 2011 Jul 25;12(11):1626-53. doi: 10.1002/cbic.201000717. Epub 2011 Jul 12.
Despite their enormous diversity in biological function and structure, peptides and proteins are endowed with properties that have induced and stimulated the development of peptidomimetics. Clearly, peptides can be considered as the "stem" of a phylogenetic molecular development tree from which branches of oligomeric peptidomimetics such as peptoids, peptidosulfonamides, urea peptidomimetics, as well as β-peptides have sprouted. It is still a challenge to efficiently synthesize these oligomeric species, and study their structural and biological properties. Combining peptides and peptidomimetics led to the emergence of peptide-peptidomimetic hybrids in which one or more (proteinogenic) amino acid residues have been replaced with these mimetic residues. In scan-like approaches, the influence of these replacements on biological activity can then be studied, to evaluate to what extent a peptide can be transformed into a peptidomimetic structure while maintaining, or even improving, its biological properties. A central issue, especially with the smaller peptides, is the lack of secondary structure. Important approaches to control secondary structure include the introduction of α,α-disubstituted amino acids, or (di)peptidomimetic structures such as the Freidinger lactam. Apart from intra-amino acid constraints, inter-amino acid constraints for formation of a diversity of cyclic peptides have shaped a thick branch. Apart from the classical disulfide bridges, the repertoire has been extended to include sulfide and triazole bridges as well as the single-, double- and even triple-bond replacements, accessible by the extremely versatile ring-closing alkene/alkyne metathesis approaches. The latter approach is now the method of choice for the secondary structure that presents the greatest challenge for structural stabilization: the α-helix.
尽管在生物学功能和结构上存在巨大差异，但肽和蛋白质具有诱导和刺激类肽物发展的特性。显然，肽可以被视为从进化分子发育树中分支出来的寡聚类肽物的“主干”，例如肽类、肽磺酰胺、脲类肽类以及β-肽类。有效地合成这些寡聚体并研究其结构和生物学特性仍然是一个挑战。将肽和类肽物结合在一起，导致肽-类肽物杂种的出现，其中一个或多个（蛋白质）氨基酸残基被这些模拟残基取代。在扫描样方法中，可以研究这些取代对生物活性的影响，以评估肽在多大程度上可以转化为类肽结构，同时保持甚至改善其生物学特性。一个核心问题，特别是对于较小的肽，是缺乏二级结构。控制二级结构的重要方法包括引入α，α-二取代氨基酸或（二）肽类物结构，如 Freidinger 内酰胺。除了氨基酸内的限制外，形成各种环肽的氨基酸间限制也形成了一个粗壮的分支。除了经典的二硫键外，还扩展了包括硫醚和三唑键以及单键、双键甚至三键的取代，这些都可以通过极其通用的环闭烯/炔烃复分解方法来实现。对于结构稳定化带来最大挑战的二级结构，后一种方法现在是首选方法：α-螺旋。
