Petrov Dimitar, Plais Louise, Schira Kristina, Cai Junyu, Keller Michelle, Lessing Alice, Bassi Gabriele, Cazzamalli Samuele, Neri Dario, Gloger Andreas, Scheuermann Jörg
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 3, 8093, Zurich, Switzerland.
Philochem AG, Libernstrasse 3, 8112, Otelfingen, Switzerland.
Nat Commun. 2025 Apr 5;16(1):3273. doi: 10.1038/s41467-025-58507-w.
Cyclic peptides constitute an important drug modality since they offer significant advantages over small molecules and macromolecules. However, access to diverse chemical sets of cyclic peptides is difficult on a large library scale. DNA-encoded Chemical Libraries (DELs) provide a suitable tool to obtain large chemical diversity, but cyclic DELs made by standard DEL implementation cannot efficiently explore their conformational diversity. On the other hand, dual-display Encoded Self-Assembling Chemical (ESAC) Libraries can be used for modulating macrocycle flexibility since the two displayed peptides can be connected in an incremental fashion. In this work, we construct a 56 million dual-display ESAC library using a two-step cyclization strategy. We show that varying the level of conformational restraint is essential for the discovery of specific ligands for the three protein targets thrombin, human alkaline phosphatase and streptavidin.
环肽是一种重要的药物形式，因为它们相对于小分子和大分子具有显著优势。然而，要在大规模文库中获取多样化的环肽化学集是很困难的。DNA编码化学文库（DELs）为获得大量化学多样性提供了一个合适的工具，但通过标准DEL实施制备的环肽DELs无法有效地探索其构象多样性。另一方面，双展示编码自组装化学（ESAC）文库可用于调节大环的灵活性，因为两个展示的肽可以以递增的方式连接。在这项工作中，我们使用两步环化策略构建了一个包含5600万个双展示ESAC文库。我们表明，改变构象限制水平对于发现针对三种蛋白质靶点凝血酶、人碱性磷酸酶和链霉亲和素的特异性配体至关重要。
