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Azanitrile Inhibitors of the SmCB1 Protease Target Are Lethal to Schistosoma mansoni: Structural and Mechanistic Insights into Chemotype Reactivity
- Source :
- ACS Infectious Diseases
- Publication Year :
- 2020
- Publisher :
- American Chemical Society, 2020.
-
Abstract
- Azapeptide nitriles are postulated to reversibly covalently react with the active-site cysteine residue of cysteine proteases and form isothiosemicarbazide adducts. We investigated the interaction of azadipeptide nitriles with the cathepsin B1 drug target (SmCB1) from Schistosoma mansoni, a pathogen that causes the global neglected disease schistosomiasis. Azadipeptide nitriles were superior inhibitors of SmCB1 over their parent carba analogs. We determined the crystal structure of SmCB1 in complex with an azadipeptide nitrile and analyzed the reaction mechanism using quantum chemical calculations. The data demonstrate that azadipeptide nitriles, in contrast to their carba counterparts, undergo a change from E- to Z-configuration upon binding, which gives rise to a highly favorable energy profile of noncovalent and covalent complex formation. Finally, azadipeptide nitriles were considerably more lethal than their carba analogs against the schistosome pathogen in culture, supporting the further development of this chemotype as a treatment for schistosomiasis.
- Subjects :
- 0301 basic medicine
Proteases
Nitrile
Stereochemistry
medicine.medical_treatment
030106 microbiology
Article
cysteine proteases
Cathepsin B
03 medical and health sciences
Residue (chemistry)
chemistry.chemical_compound
Protein structure
schistosomiasis
medicine
Animals
Reactivity (chemistry)
Protease
biology
Schistosoma mansoni
biology.organism_classification
azapeptide inhibitors
030104 developmental biology
Infectious Diseases
chemistry
protein structures
structure−activity relationships
Cysteine
Peptide Hydrolases
Subjects
Details
- Language :
- English
- ISSN :
- 23738227
- Volume :
- 7
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- ACS Infectious Diseases
- Accession number :
- edsair.doi.dedup.....e0c7375e2e725eab96a930e5400b7d91