期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 137, 期 10, 页码 3616-3621出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.5b00095
关键词
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资金
- National Institutes of Health [R01-GM054051]
- NIH Chemical Biology training grant [5T32 GM7499-34]
The protein arginine deiminases (PADs) are a family of enzymes that catalyze the post-translational hydrolytic deimination of arginine residues. Four different enzymologically active PAD subtypes have been characterized and exhibit tissue-specific expression and association with a number of different diseases. In this Article we describe the development of an approach for the reliable discovery of low molecular weight, nonpeptidic fragment substrates of the PADs that then can be optimized and converted to mechanism-based irreversible PAD inhibitors. The approach is demonstrated by the development of potent and selective inhibitors of PAD3, a PAD subtype implicated in the neurodegenerative response to spinal cord injury. Multiple structurally distinct inhibitors were identified with the most potent inhibitors having >10,000 min(-1) M-1 k(inact)/K-I values and >= 10-fold selectivity for PAD3 over PADs 1, 2, and 4.
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