Journal
CURRENT DRUG TARGETS
Volume 11, Issue 3, Pages 335-344Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/138945010790711905
Keywords
Z-DNA; Z-DNA binding protein; ADAR1; DAI (DLM-1/ZBP1); PKZ; E3L; Z alpha domain; Z beta domain; computer-aided drug design; virtual screening; scoring function
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Funding
- National Research Laboratory Program [NRL-2006-02287]
- 21C Frontier Functional Proteomics Program [FPR08B2-270]
- Ubiquitome Research Program [M10533010001-05N3301-00100]
- 21st Century Frontier RD Program [CBM33-B2000-01-02-00]
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Z-DNA, the alternative form of double-stranded DNA involved in a variety of nucleotide metabolism, is recognized and stabilized by specific Z-DNA binding proteins (ZBPs). Three ZBPs known in vertebrates -ADAR1, DAI and PKZ- modulate innate immunity, particularly, the IFN-induced immune response. The E3L protein of vaccinia virus appears to compete with the host ZBP for Z-DNA binding, thereby suppressing the host immune system. ZBPs are, therefore, considered to be attractive therapeutic targets for infectious and immune diseases. Recent advances in computer-aided drug development combined with the high-resolution crystal and NMR structures of ZBPs have enabled us to discover novel candidates for ZBP inhibitors. In this study, we present an overview of Z-DNA and known ZBPs as drug targets, and summarize recent progress in the structure-based identification of ZBP inhibitors.
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