期刊
NATURE CHEMICAL BIOLOGY
卷 5, 期 7, 页码 502-507出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.184
关键词
-
资金
- Swiss National Science Foundation (SNSF)
- Novartis Foundation
- MRC [MC_U105115240] Funding Source: UKRI
- Medical Research Council [MC_U105115240] Funding Source: researchfish
Here we describe a phage strategy for the selection of ligands based on bicyclic or linear peptides attached covalently to an organic core. We designed peptide repertoires with three reactive cysteine residues, each spaced apart by several random amino acid residues, and we fused the repertoires to the phage gene-3-protein. Conjugation with tris-(bromomethyl) benzene via the reactive cysteines generated repertoires of peptide conjugates with two peptide loops anchored to a mesitylene core. Iterative affinity selections yielded several enzyme inhibitors; after further mutagenesis and selection, we were able to chemically synthesize a lead inhibitor (PK15; K(i) = 1.5 nM) specific to human plasma kallikrein that efficiently interrupted the intrinsic coagulation pathway in human plasma tested ex vivo. This approach offers a powerful means of generating and selecting bicyclic macrocycles (or if cleaved, linear derivatives thereof) as ligands poised at the interface of small-molecule drugs and biologics.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据