Peptide inhibitors targeting Clostridium difficile toxins A and B.
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.
Abdeen
Sanofar J
SJ
Swett
Rebecca J
RJ
Feig
Andrew L
AL
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001905:Botulinum Toxins / Q000037:antagonists & inhibitors*; D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors*; D016360:Clostridioides difficile / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D010455:Peptides; D005964:Glucosyltransferases; D001905:Botulinum Toxins; D019274:Botulinum Toxins, Type A