Department of Chemistry and Chemical Biology and Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY, 12180, USA.
Institute for Protein Design, University of Washington, Seattle, WA, 98195, USA; Department of Medicinal Chemistry, University of Washington, Seattle, WA, 98195, USA.
Curr Opin Struct Biol. 2023 Jun;80:102603. doi: 10.1016/j.sbi.2023.102603. Epub 2023 May 12.
Membrane-traversing peptides offer opportunities for targeting intracellular proteins and oral delivery. Despite progress in understanding the mechanisms underlying membrane traversal in natural cell-permeable peptides, there are still several challenges to designing membrane-traversing peptides with diverse shapes and sizes. Conformational flexibility appears to be a key determinant of membrane permeability of large macrocycles. We review recent developments in the design and validation of chameleonic cyclic peptides, which can switch between alternative conformations to enable improved permeability through cell membranes, while still maintaining reasonable solubility and exposed polar functional groups for target protein binding. Finally, we discuss the principles, strategies, and practical considerations for rational design, discovery, and validation of permeable chameleonic peptides.
穿膜肽为靶向细胞内蛋白和口服递药提供了机会。尽管在理解天然细胞通透肽的穿膜机制方面取得了进展，但设计具有不同形状和大小的穿膜肽仍然存在一些挑战。构象灵活性似乎是大环类透膜性的关键决定因素。我们综述了近期在变色龙环肽的设计和验证方面的进展，这些环肽可以在不同构象之间切换，从而改善穿过细胞膜的通透性，同时仍然保持合理的溶解度和暴露的极性功能基团以结合靶蛋白。最后，我们讨论了合理设计、发现和验证透膜变色龙肽的原则、策略和实际考虑因素。
