Back to Search
Start Over
Development of Potent Inhibitors of Botulinum Neurotoxin Type B
- Source :
- Journal of Medicinal Chemistry, Journal of Medicinal Chemistry, American Chemical Society, 2003, 46 (22), pp.4648-4656. ⟨10.1021/jm0300680⟩, Journal of Medicinal Chemistry, 2003, 46 (22), pp.4648-4656. ⟨10.1021/jm0300680⟩
- Publication Year :
- 2003
- Publisher :
- HAL CCSD, 2003.
-
Abstract
- International audience; Botulinum neurotoxins are the most potent toxins known to date. They are zinc-metalloproteases able to cleave selectively an essential component of neurotransmitter exocytosis, causing the syndrome of botulism characterized by a flaccid paralysis. There is a great interest in designing antagonists of the action of these toxins. One way is to inhibit their catalytic activity. In this study, we report the design of such inhibitors directed toward BoNT/B. A study of the S(1) subsite specificity, using several beta-amino thiols, has shown that this subsite prefers a p-carboxybenzyl moiety. The specificity of the S(1)' and S(2)' subsites was studied using two libraries of pseudotripeptides containing the S(1) synthon derived from the best beta-amino thiol tested. Finally, a selection of various non natural amino acids for the recognition of the "prime" domain led to the most potent inhibitor of BoNT/B described to date with a K(i) value of 20 nM.
- Subjects :
- Models, Molecular
Botulinum Toxins
Stereochemistry
[SDV]Life Sciences [q-bio]
medicine.disease_cause
01 natural sciences
Benzoates
03 medical and health sciences
Structure-Activity Relationship
Drug Discovery
medicine
Neurotoxin
Structure–activity relationship
Botulism
Protease Inhibitors
Botulinum Toxins, Type A
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
Oligopeptide
biology
Sulfur Compounds
010405 organic chemistry
Chemistry
Metalloendopeptidases
medicine.disease
0104 chemical sciences
3. Good health
Amino acid
[SDV] Life Sciences [q-bio]
Enzyme
Biochemistry
Enzyme inhibitor
biology.protein
Molecular Medicine
Clostridium botulinum
Oligopeptides
Subjects
Details
- Language :
- English
- ISSN :
- 00222623 and 15204804
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry, Journal of Medicinal Chemistry, American Chemical Society, 2003, 46 (22), pp.4648-4656. ⟨10.1021/jm0300680⟩, Journal of Medicinal Chemistry, 2003, 46 (22), pp.4648-4656. ⟨10.1021/jm0300680⟩
- Accession number :
- edsair.doi.dedup.....1128394915d8a63326e21a162b71e888