Department of Biochemistry and Institute for Protein Design, University of Washington, Seattle, Washington 98195, United States.
J Med Chem. 2022 Sep 22;65(18):11913-11926. doi: 10.1021/acs.jmedchem.2c01077. Epub 2022 Sep 8.
Cyclic peptides are among the most diverse architectures for current drug discovery efforts. Their size, stability, and ease of synthesis provide attractive scaffolds to engage and modulate some of the most challenging targets, including protein-protein interactions and those considered to be "undruggable". With a variety of sophisticated screening technologies to produce libraries of cyclic peptides, including phage display, mRNA display, split intein circular ligation of peptides, and screening, a new era of cyclic peptide drug discovery is at the forefront of modern medicine. In this perspective, we begin by discussing cyclic peptides approved for clinical use in the past two decades. Particular focus is placed around synthetic chemistries to generate libraries of cyclic peptides and novel methods to screen them. The perspective culminates with future prospects for generating cyclic peptides as viable therapeutic options and discusses the advantages and disadvantages currently being faced with bringing them to market.
环状肽是当前药物发现工作中最具多样性的结构之一。它们的大小、稳定性和易于合成为与一些最具挑战性的靶点相互作用和调节提供了有吸引力的支架，这些靶点包括蛋白质-蛋白质相互作用和那些被认为是“不可成药”的靶点。随着各种复杂的筛选技术的出现，包括噬菌体展示、mRNA 展示、肽的分裂内含肽环化连接和筛选，可以生成环状肽文库，这标志着环状肽药物发现的新时代处于现代医学的前沿。在本观点中，我们首先讨论了过去二十年中获准用于临床的环状肽。特别关注的是用于生成环状肽文库的合成化学和筛选它们的新方法。本观点的最后是探讨将环状肽作为可行的治疗选择的未来前景，并讨论当前在将它们推向市场时所面临的优势和劣势。
