期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 6, 页码 2455-2461出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm401730y
关键词
-
资金
- Deutsther Akademischer Austausch Dienst (DAAD)
- National Institutes of Health National Research Service Award (NRSA) [F32 ES021690]
- NIH [CA102792]
- National Council for Scientific and Technological Development-CNPq
- Federal University of Minas Gerais/Brazil
- Cancer Research UK [11566] Funding Source: researchfish
Stapled helix peptides can serve as useful tools for inhibiting protein-protein interactions but can be difficult to optimize for affinity. Here we describe the discovery and optimization of a stapled helix peptide that binds to the N-terminal domain of the 70 kDa subunit of replication protein A (RPA70N). In addition to applying traditional optimization strategies, we employed a novel approach for efficiently designing peptides containing unnatural amino acids. We discovered hot spots in the target protein using a fragment-based screen, identified the amino acid that binds to the hot spot, and selected an unnatural amino acid to incorporate, based on the structure-activity relationships of small molecules that bind to this site. The resulting stapled helix peptide potently and selectively binds to RPA70N, does not disrupt ssDNA binding, and penetrates cells. This peptide may serve as a probe to explore the therapeutic potential of RPA70N inhibition in cancer.
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