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Article

A Metalloproteinase Cocktail from the Venom of Protobothrops flavoviridis Cleaves Amyloid Beta Peptides at the α-Cleavage Site

by
Eugene Futai
1,*,
Hajime Kawasaki
1,
Shinichi Sato
2,
Khadija Daoudi
1,
Masafumi Hidaka
1,
Taisuke Tomita
3 and
Tomohisa Ogawa
1
1
Laboratory of Enzymology, Graduate School of Agricultural Sciences, Tohoku University, Sendai 980-8572, Japan
2
Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai 980-8578, Japan
3
Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
*
Author to whom correspondence should be addressed.
Toxins 2023, 15(8), 500; https://doi.org/10.3390/toxins15080500
Submission received: 21 July 2023 / Revised: 7 August 2023 / Accepted: 10 August 2023 / Published: 12 August 2023
(This article belongs to the Special Issue Potential Therapeutic Applications of Animal Venoms and Toxins)
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Abstract

A disintegrin and metalloproteinase (ADAM) family proteins are a major class of membrane-anchored multidomain proteinases that are responsible for the shedding of cell surface protein ectodomains, including amyloid precursor protein (APP). Human ADAM 9, 10, and 17 proteolyze APPs and produce non-amyloid-genic p3 peptides, instead of neurotoxic amyloid-β peptides (Aβs; Aβ40 and Aβ42), which form fibrils and accumulate in the brain of patients with Alzheimer’s disease (AD). The ADAM family is closely related to snake venom metalloproteinases (SVMPs), which are derived from ancestral ADAMs but act as soluble proteinases. To test the therapeutic potential of SVMPs, we purified SVMPs from Protobothrops flavoviridis venom using metal ion affinity and pooled into a cocktail. Thus, 9 out of 11 SVMPs in the P. flavoviridis genome were identified in the cocktail. SVMPs inhibited Aβ secretion when added to human cell culture medium without affecting APP proteolysis. SVMPs degraded synthetic Aβ40 and Aβ42 peptides at the same cleavage site (α-site of APP) as ADAM9, 10, and 17. SVMPs did not degrade Aβ fibrils but interfered with their formation, assessed using thioflavin-T. Thus, SVMPs have therapeutic potential for AD as an Aβ-degrading protease, and the finding adds to the discovery of bioactive peptides from venoms as novel therapeutics.
Keywords: α-secretase; a disintegrin and metalloproteinase (ADAM); Alzheimer’s disease; amyloid beta (Aβ); amyloid precursor protein (APP); snake venom metalloproteinase (SVMP) α-secretase; a disintegrin and metalloproteinase (ADAM); Alzheimer’s disease; amyloid beta (Aβ); amyloid precursor protein (APP); snake venom metalloproteinase (SVMP)

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MDPI and ACS Style

Futai, E.; Kawasaki, H.; Sato, S.; Daoudi, K.; Hidaka, M.; Tomita, T.; Ogawa, T. A Metalloproteinase Cocktail from the Venom of Protobothrops flavoviridis Cleaves Amyloid Beta Peptides at the α-Cleavage Site. Toxins 2023, 15, 500. https://doi.org/10.3390/toxins15080500

AMA Style

Futai E, Kawasaki H, Sato S, Daoudi K, Hidaka M, Tomita T, Ogawa T. A Metalloproteinase Cocktail from the Venom of Protobothrops flavoviridis Cleaves Amyloid Beta Peptides at the α-Cleavage Site. Toxins. 2023; 15(8):500. https://doi.org/10.3390/toxins15080500

Chicago/Turabian Style

Futai, Eugene, Hajime Kawasaki, Shinichi Sato, Khadija Daoudi, Masafumi Hidaka, Taisuke Tomita, and Tomohisa Ogawa. 2023. "A Metalloproteinase Cocktail from the Venom of Protobothrops flavoviridis Cleaves Amyloid Beta Peptides at the α-Cleavage Site" Toxins 15, no. 8: 500. https://doi.org/10.3390/toxins15080500

APA Style

Futai, E., Kawasaki, H., Sato, S., Daoudi, K., Hidaka, M., Tomita, T., & Ogawa, T. (2023). A Metalloproteinase Cocktail from the Venom of Protobothrops flavoviridis Cleaves Amyloid Beta Peptides at the α-Cleavage Site. Toxins, 15(8), 500. https://doi.org/10.3390/toxins15080500

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