Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
Int J Mol Sci. 2021 Feb 5;22(4):1611. doi: 10.3390/ijms22041611.
The sheer size and vast chemical space (i.e., diverse repertoire and spatial distribution of functional groups) underlie peptides' ability to engage in specific interactions with targets of various structures. However, the inherent flexibility of the peptide chain negatively affects binding affinity and metabolic stability, thereby severely limiting the use of peptides as medicines. Imposing conformational constraints to the peptide chain offers to solve these problems but typically requires laborious structure optimization. Alternatively, libraries of constrained peptides with randomized modules can be screened for specific functions. Here, we present the properties of conformationally constrained peptides and review rigidification chemistries/strategies, as well as synthetic and enzymatic methods of producing macrocyclic peptides. Furthermore, we discuss the in vitro molecular evolution methods for the development of constrained peptides with pre-defined functions. Finally, we briefly present applications of selected constrained peptides to illustrate their exceptional properties as drug candidates, molecular recognition probes, and minimalist catalysts.
肽能够与各种结构的靶标特异性相互作用，这主要归因于其巨大的尺寸和广阔的化学空间（即，功能基团的多样 repertoire 和空间分布）。然而，肽链的固有灵活性会对结合亲和力和代谢稳定性产生负面影响，从而严重限制了肽作为药物的应用。对肽链施加构象约束为解决这些问题提供了可能，但通常需要繁琐的结构优化。或者，可以筛选具有随机模块的约束肽文库以获得特定功能。本文介绍了构象约束肽的特性，并综述了刚性化学/策略，以及产生大环肽的合成和酶法。此外，我们还讨论了体外分子进化方法在开发具有预定义功能的约束肽方面的应用。最后，我们简要介绍了选定约束肽的应用，以说明它们作为候选药物、分子识别探针和最小化催化剂的特殊性质。
