Peptide Inhibitors Targeting Clostridium difficile Toxins A and B

• Published in: ACS chemical biology 2010-12, Vol.5 (12), p.1097-1103
• Main Authors: Abdeen, Sanofar J, Swett, Rebecca J, Feig, Andrew L
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Botulinum Toxins - antagonists & inhibitors; Botulinum Toxins, Type A - antagonists & inhibitors; Clostridium difficile - drug effects; Clostridium difficile - enzymology; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Glucosyltransferases - antagonists & inhibitors; Models, Molecular; Peptides - chemistry; Peptides - pharmacology; Protein Structure, Tertiary
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/cb100209b

Clostridium difficile causes severe hospital-acquired antibiotic-associated diarrhea due to the activity of two large protein toxins. Current treatments suffer from a high relapse rate and are generating resistant strains; thus new methods of dealing with these infections that target the virulence factors directly are of interest. Phage display was used to identify peptides that bind to the catalytic domain of C. difficile Toxin A. Library screening and subsequent quantitative binding and inhibition studies showed that several of these peptides are potent inhibitors. Fragment-based computational docking of these peptides elucidated the binding modes within the active site. These antitoxin peptides may serve as potential lead compounds to further engineer peptidomimetic inhibitors of the clostridial toxins.