Neutralising effects of small molecule toxin inhibitors on nanofractionated coagulopathic Crotalinae snake venoms

Autor: Freek J. Vonk, Govert W. Somsen, Nicholas R. Casewell, Julien Slagboom, Jeroen Kool, Laura-Oana Albulescu, Chunfang Xie
Přispěvatelé: BioAnalytical Chemistry, AIMMS, Chemistry and Pharmaceutical Sciences
Jazyk: angličtina
Rok vydání: 2020
Předmět:
qu_136
Antivenom
Venom
Pharmacology
DMSO
dimethyl sulfoxide
HTS
high-throughput screening
SVMP
snake venom metalloproteinase
TIC
total ion current
chemistry.chemical_compound
0302 clinical medicine
NOI
no observed inhibition
Snakebite
General Pharmacology
Toxicology and Pharmaceutics
PN
partly neutralised at 20 μmol/L inhibitor concentrations
FA
formic acid
wh_310
0303 health sciences
biology
Chemistry
LC
liquid chromatography
Snake venom
SVSP
snake venom serine protease
030220 oncology & carcinogenesis
CTL
C-type lectins
Original Article
Dimercaprol
Marimastat
medicine.drug
wd_410
Proteases
Bothrops jararaca
Chelators
Nanofractionation
complex mixtures
WHO
World Health Organization
03 medical and health sciences
PBS
phosphate buffered saline
SDG 3 - Good Health and Well-being
medicine
Varespladib
030304 developmental biology
lcsh:RM1-950
PLA2
phospholipase A2
qv_195
ACN
acetonitrile
biology.organism_classification
lcsh:Therapeutics. Pharmacology
MS
mass spectrometry
XIC
extracted ion current
Zdroj: Acta Pharmaceutica Sinica B, 10(10), 1835-1845. Elsevier BV
Acta Pharmaceutica Sinica. B
Xie, C, Slagboom, J, Albulescu, L O, Somsen, G W, Vonk, F J, Casewell, N R & Kool, J 2020, ' Neutralising effects of small molecule toxin inhibitors on nanofractionated coagulopathic Crotalinae snake venoms ', Acta Pharmaceutica Sinica B, vol. 10, no. 10, pp. 1835-1845 . https://doi.org/10.1016/j.apsb.2020.09.005
Acta Pharmaceutica Sinica B, Vol 10, Iss 10, Pp 1835-1845 (2020)
ISSN: 2211-3835
DOI: 10.1016/j.apsb.2020.09.005
Popis: Repurposing small molecule drugs and drug candidates is considered as a promising approach to revolutionise the treatment of snakebite envenoming. In this study, we investigated the inhibiting effects of the small molecules varespladib (nonspecific phospholipase A2 inhibitor), marimastat (broad spectrum matrix metalloprotease inhibitor) and dimercaprol (metal ion chelator) against coagulopathic toxins found in Crotalinae (pit vipers) snake venoms. Venoms from Bothrops asper, Bothrops jararaca, Calloselasma rhodostoma and Deinagkistrodon acutus were separated by liquid chromatography, followed by nanofractionation and mass spectrometry identification undertaken in parallel. Nanofractions of the venom toxins were then subjected to a high-throughput coagulation assay in the presence of different concentrations of the small molecules under study. Anticoagulant venom toxins were mostly identified as phospholipases A2, while procoagulant venom activities were mainly associated with snake venom metalloproteinases and snake venom serine proteases. Varespladib was found to effectively inhibit most anticoagulant venom effects, and also showed some inhibition against procoagulant toxins. Contrastingly, marimastat and dimercaprol were both effective inhibitors of procoagulant venom activities but showed little inhibitory capability against anticoagulant toxins. The information obtained from this study aids our understanding of the mechanisms of action of toxin inhibitor drug candidates, and highlights their potential as future snakebite treatments.
Graphical abstract This study investigated the small molecule inhibitors varespladib, marimastat and dimercaprol in neutralising coagulopathic Crotalinae (pit vipers) snake venom toxins by using nanofractionation analytics which combines bioassays, liquid chromatography and mass spectrometry in parallel. Results obtained highlight their potential as future snakebite treatments.Image 1
Databáze: OpenAIRE
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