title: Peptide inhibitors of botulinum neurotoxin serotype A: design, inhibition, cocrystal structures, structure-activity relationship and pharmacophore modeling.
abstract: Clostridium botulinum neurotoxins are classified as Category A bioterrorism agents by the Centers for Disease Control and Prevention (CDC). The seven serotypes (A-G) of the botulinum neurotoxin, the causative agent of the disease botulism, block neurotransmitter release by specifically cleaving one of the three SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and induce flaccid paralysis. Using a structure-based drug-design approach, a number of peptide inhibitors were designed and their inhibitory activity against botulinum serotype A (BoNT/A) protease was determined. The most potent peptide, RRGF, inhibited BoNT/A protease with an IC(50) of 0.9 µM and a K(i) of 358 nM. High-resolution crystal structures of various peptide inhibitors in complex with the BoNT/A protease domain were also determined. Based on the inhibitory activities and the atomic interactions deduced from the cocrystal structures, the structure-activity relationship was analyzed and a pharmacophore model was developed. Unlike the currently available models, this pharmacophore model is based on a number of enzyme-inhibitor peptide cocrystal structures and improved the existing models significantly, incorporating new features.
authors.affiliation: Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
authors.forename: Gyanendra
authors.initials: G
authors.lastname: Kumar
authors.forename: Desigan
authors.initials: D
authors.lastname: Kumaran
authors.forename: S Ashraf
authors.initials: SA
authors.lastname: Ahmed
authors.forename: Subramanyam
authors.initials: S
authors.lastname: Swaminathan
mesh_terms: D019274:Botulinum Toxins, Type A / Q000037:antagonists & inhibitors*; D001906:Botulism / Q000188:drug therapy; D003014:Clostridium botulinum / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D009498:Neurotoxins / Q000037:antagonists & inhibitors*; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D009498:Neurotoxins; D010455:Peptides; D011480:Protease Inhibitors; D010447:Peptide Hydrolases; D019274:Botulinum Toxins, Type A