{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:01:18Z","timestamp":1788415278788,"version":"build-2803163510"},"reference-count":57,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T00:00:00Z","timestamp":1670284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Universidad de Antioquia","award":["CIQF-319"],"award-info":[{"award-number":["CIQF-319"]}]},{"name":"Estrategia de Sostenibilidad","award":["CIQF-319"],"award-info":[{"award-number":["CIQF-319"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Snakebite is a neglected tropical disease that causes extensive mortality and morbidity in rural communities. Antivenim sera are the currently approved therapy for snake bites; however, they have some therapeutic limitations that have been extensively documented. Recently, small molecule toxin inhibitors have received significant attention as potential alternatives or co-adjuvant to immunoglobulin-based snakebite therapies. Thus, in this study, we evaluated the inhibitory effects of the phospholipase A2 inhibitor varespladib and the metalloproteinase inhibitor CP471474 and their synergistic effects on the lethal, edema-forming, hemorrhagic, and myotoxic activities of Bothrops asper and Crotalus durissus cumanensis venoms from Colombia. Except for the preincubation assay of the lethal activity with B. asper venom, the mixture showed the best inhibitory activity. Nevertheless, the mix did not display statistically significant differences to varespladib and CP471474 used separately in all assays. In preincubation assays, varespladib showed the best inhibitory activity against the lethal effect induced by B. asper venom. However, in independent injection assays, the mix of the compounds partially inhibited the lethal activity of both venoms (50%). In addition, in the assays to test the inhibition of edema-forming activity, the mixture exhibited the best inhibitory activity, followed by Varespladib, but without statistically significant differences (p &gt; 0.05). The combination also decreased the myotoxic activity of evaluated venoms. In these assays, the mix showed statistical differences regarding CP471474 (p &lt; 0.05). The mixture also abolished the hemorrhagic activity of B. asper venom in preincubation assays, with no statistical differences to CP471474. Finally, the mixture showed inhibition in studies with independent administration in a time-dependent manner. To propose a mode of action of varespladib and CP471474, molecular docking was performed. PLA2s and SVMPs from tested venoms were used as targets. In all cases, our molecular modeling results suggested that inhibitors may occupy the substrate-binding cleft of the enzymes, which was supported by specific interaction with amino acids from the active site, such as His48 for PLA2s and Glu143 for the metalloproteinase. In addition, varespladib and CP471474 also showed interaction with residues from the hydrophobic channel in PLA2s and substrate binding subsites in the SVMP. Our results suggest a synergistic action of the mixed inhibitors and show the potential of varespladib, CP471474, and their mixture to generate new treatments for snakebite envenoming with application in the field or as antivenom co-adjuvants.<\/jats:p>","DOI":"10.3390\/molecules27238588","type":"journal-article","created":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T02:23:42Z","timestamp":1670293422000},"page":"8588","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Inhibitory Effects of Varespladib, CP471474, and Their Potential Synergistic Activity on Bothrops asper and Crotalus durissus cumanensis Venoms"],"prefix":"10.3390","volume":"27","author":[{"given":"Sara","family":"Quiroz","sequence":"first","affiliation":[{"name":"Research Group in Toxinology, Pharmaceutical, and Food Alternatives, Pharmaceutical and Food Sciences Faculty, University of Antioquia, Medell\u00edn 50010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1893-2191","authenticated-orcid":false,"given":"Isabel C.","family":"Henao Casta\u00f1eda","sequence":"additional","affiliation":[{"name":"Research Group in Marine Natural Products, Pharmaceutical and Food Sciences Faculty, University of Antioquia, Medell\u00edn 050010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3851-2752","authenticated-orcid":false,"given":"Johan","family":"Granados","sequence":"additional","affiliation":[{"name":"Research Group in Pharmaceutical Promotion and Prevention, Universidad de Antioquia, Medell\u00edn 050010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arley Camilo","family":"Pati\u00f1o","sequence":"additional","affiliation":[{"name":"Research Group in Toxinology, Pharmaceutical, and Food Alternatives, Pharmaceutical and Food Sciences Faculty, University of Antioquia, Medell\u00edn 50010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3096-2134","authenticated-orcid":false,"given":"Lina Mar\u00eda","family":"Preciado","sequence":"additional","affiliation":[{"name":"Research Group in Toxinology, Pharmaceutical, and Food Alternatives, Pharmaceutical and Food Sciences Faculty, University of Antioquia, Medell\u00edn 50010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9612-2827","authenticated-orcid":false,"given":"Jaime Andr\u00e9s","family":"Perea\u00f1ez","sequence":"additional","affiliation":[{"name":"Research Group in Toxinology, Pharmaceutical, and Food Alternatives, Pharmaceutical and Food Sciences Faculty, University of Antioquia, Medell\u00edn 50010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17063","DOI":"10.1038\/nrdp.2017.63","article-title":"Snakebite Envenoming","volume":"3","author":"Calvete","year":"2017","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kasturiratne, A., Wickremasinghe, A.R., de Silva, N., Gunawardena, N.K., Pathmeswaran, A., Premaratna, R., Savioli, L., Lalloo, D.G., and de Silva, H.J. (2008). The Global Burden of Snakebite: A Literature Analysis and Modelling Based on Regional Estimates of Envenoming and Deaths. PLoS Med., 5.","DOI":"10.1371\/journal.pmed.0050218"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"100074","DOI":"10.1016\/j.toxcx.2021.100074","article-title":"Chronic Health Effects and Cost of Snakebite","volume":"9\u201310","author":"Kasturiratne","year":"2021","journal-title":"Toxicon X"},{"key":"ref_4","first-page":"38","article-title":"New approaches & technologies of venomics to meet the challenge of human envenoming by snakebites in India","volume":"138","author":"Warrell","year":"2013","journal-title":"Indian J. Med. Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"G\u00f3mez-Betancur, I., Gogineni, V., Salazar-Ospina, A., and Le\u00f3n, F. (2019). Perspective on the Therapeutics of Anti-Snake Venom. Molecules, 24.","DOI":"10.3390\/molecules24183276"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"(2017). The Lancet Snake-Bite Envenoming: A Priority Neglected Tropical Disease. Lancet, 390, 2.","DOI":"10.1016\/S0140-6736(17)31751-8"},{"key":"ref_7","unstructured":"(2022, September 24). Boletin Epidemiol\u00f3gico Semana 52 del 2021, Available online: https:\/\/www.ins.gov.co\/buscador-eventos\/BoletinEpidemiologico\/2022_Bolet%C3%ADn_epidemiologico_semana_27.pdf."},{"key":"ref_8","unstructured":"Gopalakrishnakone, P., Faiz, S.M.A., Gnanathasan, C.A., Habib, A.G., Fernando, R., and Yang, C.-C. (2014). Snake Bites in Colombia. Clinical Toxinology, Springer."},{"key":"ref_9","first-page":"e202","article-title":"Epidemiology of Snakebites in Colombia (2008\u20132016)","volume":"22","year":"2020","journal-title":"Rev. Salud P\u00fablica"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3556","DOI":"10.1021\/pr800332p","article-title":"Snake Venomics of the Lancehead Pitviper Bothrops asper:  Geographic, Individual, and Ontogenetic Variations","volume":"7","author":"Sanz","year":"2008","journal-title":"J. Proteome Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"103945","DOI":"10.1016\/j.jprot.2020.103945","article-title":"Venom Variation in Bothrops asper Lineages from North-Western South America","volume":"229","author":"Pla","year":"2020","journal-title":"J. Proteom."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Quintana-Castillo, J., Vargas, L., Segura, C., Estrada-G\u00f3mez, S., Bueno-S\u00e1nchez, J., and Alarc\u00f3n, J. (2018). Characterization of the Venom of C. d. Cumanesis of Colombia: Proteomic Analysis and Antivenomic Study. Toxins, 10.","DOI":"10.3390\/toxins10020085"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1111\/j.1476-5381.1977.tb07553.x","article-title":"The mode of action at the mouse neuromuscular junction of the phospholipase a-crotapotin complex isolated from venom of the south american rattlesnake","volume":"61","author":"Hawgood","year":"1977","journal-title":"Br. J. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.toxicon.2009.01.021","article-title":"Biochemical and Biological Characterization of a PLA2 from Crotoxin Complex of Crotalus durissus cumanensis","volume":"53","author":"Marangoni","year":"2009","journal-title":"Toxicon"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.jmgm.2012.01.004","article-title":"Relationship between the Structure and the Enzymatic Activity of Crotoxin Complex and Its Phospholipase A2 Subunit: An in Silico Approach","volume":"35","year":"2012","journal-title":"J. Mol. Graph. Model."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2935","DOI":"10.2174\/138161207782023784","article-title":"Trends in Snakebite Envenomation Therapy: Scien tific, Technological and Public Health Considerations","volume":"13","author":"Gutierrez","year":"2007","journal-title":"CPD"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1042\/BST20190739","article-title":"Current Research into Snake Antivenoms, Their Mechanisms of Action and Applications","volume":"48","author":"Silva","year":"2020","journal-title":"Biochem. Soc. Trans."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"100079","DOI":"10.1016\/j.toxcx.2021.100079","article-title":"Clinical Management of Snakebite Envenoming: Future Perspectives","volume":"11","author":"Hamza","year":"2021","journal-title":"Toxicon X"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"(2011). Varespladib. Am. J. Cardiovasc. Drugs, 11, 137\u2013143.","DOI":"10.2165\/11533650-000000000-00000"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1001\/jama.2013.282836","article-title":"Varespladib and Cardiovascular Events in Patients with an Acute Coronary Syndrome: The VISTA-16 Randomized Clinical Trial","volume":"311","author":"Nicholls","year":"2014","journal-title":"JAMA"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lewin, M., Samuel, S., Merkel, J., and Bickler, P. (2016). Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation. Toxins, 8.","DOI":"10.3390\/toxins8090248"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Lewin, M., Guti\u00e9rrez, J., Samuel, S., Herrera, M., Bryan-Quir\u00f3s, W., Lomonte, B., Bickler, P., Bulfone, T., and Williams, D. (2018). Delayed Oral LY333013 Rescues Mice from Highly Neurotoxic, Lethal Doses of Papuan Taipan (Oxyuranus scutellatus) Venom. Toxins, 10.","DOI":"10.3390\/toxins10100380"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Lewin, M., Gilliam, L., Gilliam, J., Samuel, S., Bulfone, T., Bickler, P., and Guti\u00e9rrez, J. (2018). Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom. Toxins, 10.","DOI":"10.3390\/toxins10110479"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.toxicon.2018.11.292","article-title":"Neutralizing Properties of LY315920 toward Snake Venom Group I and II Myotoxic Phospholipases A2","volume":"157","author":"Lewin","year":"2019","journal-title":"Toxicon"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"129913","DOI":"10.1016\/j.bbagen.2021.129913","article-title":"The Synthetic Varespladib Molecule Is a Multi-Functional Inhibitor for PLA2 and PLA2-like Ophidic Toxins","volume":"1865","author":"Salvador","year":"2021","journal-title":"Biochim. Biophys. Acta (BBA)-Gen. Subj."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"752442","DOI":"10.3389\/fimmu.2021.752442","article-title":"The Relative Efficacy of Chemically Diverse Small-Molecule Enzyme-Inhibitors against Anticoagulant Activities of African Spitting Cobra (Naja Species) Venoms","volume":"12","author":"Chowdhury","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.toxlet.2022.06.009","article-title":"The Relative Efficacy of Chemically Diverse Small-Molecule Enzyme-Inhibitors against Anticoagulant Activities of Black Snake (Pseudechis Spp.) Venoms","volume":"366","author":"Chowdhury","year":"2022","journal-title":"Toxicol. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Youngman, N.J., Lewin, M.R., Carter, R., Naude, A., and Fry, B.G. (2022). Efficacy and Limitations of Chemically Diverse Small-Molecule Enzyme-Inhibitors against the Synergistic Coagulotoxic Activities of Bitis Viper Venoms. Molecules, 27.","DOI":"10.3390\/molecules27051733"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Xie, C., Albulescu, L.-O., Still, K.B.M., Slagboom, J., Zhao, Y., Jiang, Z., Somsen, G.W., Vonk, F.J., Casewell, N.R., and Kool, J. (2020). Varespladib Inhibits the Phospholipase A2 and Coagulopathic Activities of Venom Components from Hemotoxic Snakes. Biomedicines, 8.","DOI":"10.3390\/biomedicines8060165"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1378\/chest.123.5.1633","article-title":"Matrix Metalloproteinases Inhibition Attenuates Tobacco Smoke-Induced Emphysema in Guinea Pigs","volume":"123","author":"Selman","year":"2003","journal-title":"Chest"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Preciado, L.M., Perea\u00f1ez, J.A., and Comer, J. (2019). Potential of Matrix Metalloproteinase Inhibitors for the Treatment of Local Tissue Damage Induced by a Type P-I Snake Venom Metalloproteinase. Toxins, 12.","DOI":"10.3390\/toxins12010008"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6094","DOI":"10.1038\/s41467-020-19981-6","article-title":"A Therapeutic Combination of Two Small Molecule Toxin Inhibitors Provides Broad Preclinical Efficacy against Viper Snakebite","volume":"11","author":"Albulescu","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1586\/epr.11.61","article-title":"Proteomic tools against the neglected pathology of snake bite envenoming","volume":"8","author":"Calvete","year":"2011","journal-title":"Expert Rev. Proteom."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1016\/j.febslet.2009.03.029","article-title":"Venoms, Venomics, Antivenomics","volume":"583","author":"Calvete","year":"2009","journal-title":"FEBS Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3928","DOI":"10.1038\/s41467-018-06086-4","article-title":"In Vivo Neutralization of Dendrotoxin-Mediated Neurotoxicity of Black Mamba Venom by Oligoclonal Human IgG Antibodies","volume":"9","author":"Laustsen","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.cbi.2014.06.015","article-title":"The Biflavonoid Morelloflavone Inhibits the Enzymatic and Biological Activities of a Snake Venom Phospholipase A2","volume":"220","author":"Osorio","year":"2014","journal-title":"Chem.-Biol. Interact."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4544","DOI":"10.1111\/j.1742-4658.2011.08115.x","article-title":"Enzymatic Toxins from Snake Venom: Structural Characterization and Mechanism of Catalysis","volume":"278","author":"Kang","year":"2011","journal-title":"FEBS J."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Guti\u00e9rrez, J.M., Lewin, M.R., Williams, D.J., and Lomonte, B. (2020). Varespladib (LY315920) and Methyl Varespladib (LY333013) Abrogate or Delay Lethality Induced by Presynaptically Acting Neurotoxic Snake Venoms. Toxins, 12.","DOI":"10.3390\/toxins12020131"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.toxicon.2021.09.009","article-title":"Varespladib (LY315920) Prevents Neuromuscular Blockage and Myotoxicity Induced by Crotoxin on Mouse Neuromuscular Preparations","volume":"202","author":"Maciel","year":"2021","journal-title":"Toxicon"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"812295","DOI":"10.3389\/fphar.2021.812295","article-title":"Action of Varespladib (LY-315920), a Phospholipase A2 Inhibitor, on the Enzymatic, Coagulant and Haemorrhagic Activities of Lachesis muta rhombeata (South-American Bushmaster) Venom","volume":"12","author":"Gutierres","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Wang, Y., Zhang, J., Zhang, D., Xiao, H., Xiong, S., and Huang, C. (2018). Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation. Molecules, 23.","DOI":"10.3390\/molecules23020391"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1126\/science.2274785","article-title":"Interfacial Catalysis: The Mechanism of Phospholipase A2","volume":"250","author":"Scott","year":"1990","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2613","DOI":"10.1021\/cr990139w","article-title":"Interfacial Enzymology: The Secreted Phospholipase A2-Paradigm","volume":"101","author":"Berg","year":"2001","journal-title":"Chem. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.cbpa.2006.08.015","article-title":"Coupling of the I-Face and the Active Site of Phospholipase A2 for Interfacial Activation","volume":"10","author":"Jain","year":"2006","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.cardiores.2005.12.002","article-title":"Structure and Function of Matrix Metalloproteinases and TIMPs","volume":"69","author":"Nagase","year":"2006","journal-title":"Cardiovasc. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.toxicon.2020.08.016","article-title":"Edema, Hyperalgesia and Myonecrosis Induced by Brazilian Bothropic Venoms: Overview of the Last Decade","volume":"187","author":"Mamede","year":"2020","journal-title":"Toxicon"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/j.toxicon.2009.01.038","article-title":"Experimental Pathology of Local Tissue Damage Induced by Bothrops asper Snake Venom","volume":"54","author":"Rucavado","year":"2009","journal-title":"Toxicon"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Guti\u00e9rrez, J.M., Solano, G., Pla, D., Herrera, M., Segura, \u00c1., Vargas, M., Villalta, M., S\u00e1nchez, A., Sanz, L., and Lomonte, B. (2017). Preclinical Evaluation of the Efficacy of Antivenoms for Snakebite Envenoming: State-of-the-Art and Challenges Ahead. Toxins, 9.","DOI":"10.3390\/toxins9050163"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/BF00916097","article-title":"Host Response to Bothrops asper Snake Venom. Analysis of Edema Formation, Inflammatory Cells, and Cytokine Release in a Mouse Model","volume":"17","author":"Lomonte","year":"1993","journal-title":"Inflammation"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/0041-0101(86)90089-9","article-title":"Isolation and Partial Characterization of a Myotoxin from the Venom of the Snake Bothrops nummifer","volume":"24","author":"Lomonte","year":"1986","journal-title":"Toxicon"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"43","DOI":"10.7883\/yoken1952.13.43","article-title":"Studies on the Quantitative Method for Determination of Hemorrhagic Activity of Habu Snake Venom","volume":"13","author":"Kondo","year":"1960","journal-title":"Jpn. J. Med. Sci. Biol."},{"key":"ref_52","unstructured":"Dennington, R., Keith, T., and Millam, J. (2009). Gauss View, Version 5, Semichem Inc."},{"key":"ref_53","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., and Cheeseman, J.R. (2010). Gaussian 09, Revision, B.01, Gaussian, Inc."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/0014-4800(84)90054-6","article-title":"Pathogenesis of Myonecrosis Induced by Crude Venom and a Myotoxin of Bothrops asper","volume":"40","author":"Ownby","year":"1984","journal-title":"Exp. Mol. Pathol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1006\/exmp.1995.1042","article-title":"Local Tissue Damage Induced by BaP1, a Metalloproteinase Isolated from Bothrops asper (Terciopelo) Snake Venom","volume":"63","author":"Rucavado","year":"1995","journal-title":"Exp. Mol. Pathol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.toxicon.2010.01.011","article-title":"Crotoxin: Novel Activities for a Classic \u03b2-Neurotoxin","volume":"55","author":"Sampaio","year":"2010","journal-title":"Toxicon"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/23\/8588\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:34:41Z","timestamp":1760146481000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/23\/8588"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,6]]},"references-count":57,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["molecules27238588"],"URL":"https:\/\/doi.org\/10.3390\/molecules27238588","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,6]]}}}