| Inhibition of anthrax lethal factor: lability of hydroxamate as a chelating group. | |
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MedLine Citation:
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PMID: 22270239 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The metalloprotease activity of lethal factor (LF) from Bacillus anthracis (B. anthracis) is a main source of toxicity in the lethality of anthrax infection. Thus, the understanding of the enzymatic activity and inhibition of B. anthracis LF is of scientific and clinical interests. We have designed, synthesized, and studied a peptide inhibitor of LF, R9LF-1, with the structure NH(2)-(D: -Arg)(9)-Val-Leu-Arg-CO-NHOH in which the C-terminal hydroxamic acid is commonly used in the inhibitors of metalloproteases to chelate the active-site zinc. This inhibitor was shown to be very stable in solution and effectively inhibited LF in kinetic assays. However, its protection on murine macrophages against lethal toxin's lysis activity was relatively weak in longer assays. We further observed that the hydroxamic acid group in R9LF-1 was hydrolyzed by LF, and the hydrolytic product of this inhibitor is considerably weaker in inhibition of potency. To resist this unique hydrolytic activity of LF, we further designed a new inhibitor R9LF-2 which contained the same structure as R9LF-1 except replacing the hydroxamic acid group with N,O-dimethyl hydroxamic acid (DMHA), -N(CH(3))-O-CH(3). R9LF-2 was not hydrolyzed by LF in long-term incubation. It has a high inhibitory potency vs. LF with an inhibition constant of 6.4 nM had a better protection of macrophages against LF toxicity than R9LF-1. These results suggest that in the development of new LF inhibitors, the stability of the chelating group should be carefully examined and that DMHA is a potentially useful moiety to be used in new LF inhibitors. |
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Authors:
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Feng Li; Irina Chvyrkova; Simon Terzyan; Nancy Wakeham; Robert Turner; Arun K Ghosh; Xuejun C Zhang; Jordan Tang |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-01-25 |
Journal Detail:
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Title: Applied microbiology and biotechnology Volume: 94 ISSN: 1432-0614 ISO Abbreviation: Appl. Microbiol. Biotechnol. Publication Date: 2012 May |
Date Detail:
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Created Date: 2012-04-30 Completed Date: 2012-08-15 Revised Date: 2013-05-03 |
Medline Journal Info:
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Nlm Unique ID: 8406612 Medline TA: Appl Microbiol Biotechnol Country: Germany |
Other Details:
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Languages: eng Pagination: 1041-9 Citation Subset: IM |
Affiliation:
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Protein Studies Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. fengli6870@gmail.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antigens, Bacterial Antitoxins / metabolism* Bacterial Toxins / antagonists & inhibitors* Cells, Cultured Chelating Agents / metabolism* Hydroxamic Acids / metabolism* Kinetics Macrophages / drug effects Mice Peptides / metabolism Protease Inhibitors / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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U19 AI062629/AI/NIAID NIH HHS; U19 AI062629/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antigens, Bacterial; 0/Antitoxins; 0/Bacterial Toxins; 0/Chelating Agents; 0/Hydroxamic Acids; 0/Peptides; 0/Protease Inhibitors; 0/anthrax toxin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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