Skip to main content
SpringerLink
Log in

Myotoxin Inhibitors

  • Living reference work entry
  • First Online:
Toxins and Drug Discovery

Part of the book series: Toxinology ((TOXI))

Abstract

Myonecrosis is an important medical complication in snake envenoming and, in severe cases, can lead to drastic sequelae, such as inability and permanent tissue loss. Although the traditional serum therapy effectively neutralizes the systemic effects induced by snake venoms, there are some limitations in reversing the local symptoms induced by myotoxins, since they are small- and medium-sized proteins of low immunogenicity. Due to this impairment in current snakebite treatment, there has been an increasing interest in the search for naturally occurring molecules, as well as in the design of synthetic compounds, which are able to inhibit the main pathophysiological effects induced by snake venom PLA2 and other myotoxins. These inhibitory molecules are mainly obtained from animal blood and plant extracts; however, a diversity of other sources of myotoxin inhibitors has also been described. This chapter aims to provide current information regarding the diversity of natural and synthetic PLA2 inhibitors described so far. Moreover, a better understanding of the mechanisms of action involved in PLA2 inhibition may generate perspectives to the use of these molecules leading to the development of novel therapeutic approaches for snakebite management.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Angulo Y, Lomonte B. Inhibitory effect of fucoidan on the activities of crotaline snake venom myotoxic phospholipases A(2). Biochem Pharmacol. 2003;66(10):1993–2000.

    Article  CAS  PubMed  Google Scholar 

  • Biondo R, Pereira AMS, Marcussi S, Pereira PS, França SC, Soares AM. Inhibition of enzymatic and pharmacological activities of some snake venoms and toxins by Mandevilla velutina (Apocynaceae) aqueous extract. Biochimie. 2003;85(10):1017–25.

    Article  CAS  PubMed  Google Scholar 

  • Borges MH, Soares AM, Rodrigues VM, Andrião-Escarso SH, Diniz H, Hamaguchi A, et al. Effects of aqueous extract of Casearia sylvestris (Flacourtiaceae) on actions of snake and bee venoms and on activity of phospholipases A2. Comp Biochem Physiol B Biochem Mol Biol. 2000;127(1):21–30.

    Article  CAS  PubMed  Google Scholar 

  • Borges MH, Alves DLF, Raslan DS, Piló-Veloso D, Rodrigues VM, Homsi-Brandeburgo MI, et al. Neutralizing properties of Musa paradisiaca L. (Musaceae) juice on phospholipase A2, myotoxic, hemorrhagic and lethal activities of crotalidae venoms. J Ethnopharmacol. 2005;98(1–2):21–9.

    Article  CAS  PubMed  Google Scholar 

  • Calderón L, Lomonte B. Inhibition of the myotoxic activity of Bothrops asper myotoxin II in mice by immunization with its synthetic 13-mer peptide 115–129. Toxicon. 1999;37(4):683–7.

    Article  PubMed  Google Scholar 

  • Cavalcante WL, Campos TO, Dal Pai-Silva M, Pereira PS, Oliveira CZ, Soares AM, et al. Neutralization of snake venom phospholipase A2 toxins by aqueous extract of Casearia sylvestris (Flacourtiaceae) in mouse neuromuscular preparation. J Ethnopharmacol. 2007;112(3):490–7.

    Article  CAS  PubMed  Google Scholar 

  • Chandra V, Jasti J, Kaur P, Betzel C, Srinivasan A, Singh TP. First structural evidence of a specific inhibition of phospholipase A2 by alpha-tocopherol (vitamin E) and its implications in inflammation: crystal structure of the complex formed between phospholipase A2 and alpha-tocopherol at 1.8 A resolution. J Mol Biol. 2002a;320(2):215–22.

    Article  CAS  PubMed  Google Scholar 

  • Chandra V, Jasti J, Kaur P, Srinivasan A, Betzel C, Singh TP. Structural basis of phospholipase A2 inhibition for the synthesis of prostaglandins by the plant alkaloid aristolochic acid from a 1.7 A crystal structure. Biochemistry (Mosc). 2002b;41(36):10914–9.

    Article  CAS  Google Scholar 

  • Chandra DN, Prasanth GK, Singh N, Kumar S, Jithesh O, Sadasivan C, et al. Identification of a novel and potent inhibitor of phospholipase A(2) in a medicinal plant: crystal structure at 1.93Å and Surface Plasmon Resonance analysis of phospholipase A(2) complexed with berberine. Biochim Biophys Acta. 2011;1814(5):657–63.

    Article  CAS  PubMed  Google Scholar 

  • Chandrashekara KT, Nagaraju S, Nandini SU, Basavaiah, Kemparaju K. Neutralization of local and systemic toxicity of Daboia russelii venom by Morus alba plant leaf extract. Phytother Res PTR. 2009;23(8):1082–7.

    Article  CAS  PubMed  Google Scholar 

  • Chethankumar M, Srinivas L. New biological activity against phospholipase A2 by Turmerin, a protein from Curcuma longa L. Biol Chem. 2008;389(3):299–303.

    Article  CAS  PubMed  Google Scholar 

  • Cotrim CA, de Oliveira SCB, Diz Filho EBS, Fonseca FV, Baldissera Jr L, Antunes E, et al. Quercetin as an inhibitor of snake venom secretory phospholipase A2. Chem Biol Interact. 2011;189(1–2):9–16.

    Article  CAS  PubMed  Google Scholar 

  • Da Silva SL, Calgarotto AK, Chaar JS, Marangoni S. Isolation and characterization of ellagic acid derivatives isolated from Casearia sylvestris SW aqueous extract with anti-PLA(2) activity. Toxicon. 2008;52(6):655–66.

    Article  PubMed  Google Scholar 

  • De Alvarenga ES, Silva SA, Barosa LCA, Demuner AJ, Parreira AG, Ribeiro RIMA, et al. Synthesis and evaluation of sesquiterpene lactone inhibitors of phospholipase A2 from Bothrops jararacussu. Toxicon. 2011;57(1):100–8.

    Article  PubMed  Google Scholar 

  • Dennis EA, Cao J, Hsu YH, Magrioti V, Kokotos G. Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention. Chem Rev. 2011;111(10):6130–85.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dharmappa KK, Kumar RV, Nataraju A, Mohamed R, Shivaprasad HV, Vishwanath BS. Anti-inflammatory activity of oleanolic acid by inhibition of secretory phospholipase A2. Planta Med. 2009;75(3):211–5.

    Article  CAS  PubMed  Google Scholar 

  • Diogo LC, Fernandes RS, Marcussi S, Menaldo DL, Roberto PG, Matrangulo PVF, et al. Inhibition of snake venoms and phospholipases A(2) by extracts from native and genetically modified Eclipta alba: isolation of active coumestans. Basic Clin Pharmacol Toxicol. 2009;104(4):293–9.

    Article  CAS  PubMed  Google Scholar 

  • Dos Santos RMM, Oliveira LC, Estevão-Costa MI, de Lima ME, Santoro MM, Fortes-Dias CL. Inhibition of crotoxin binding to synaptosomes by a receptor-like protein from Crotalus durissus terrificus (the South American rattlesnake). Biochim Biophys Acta. 2005;1717(1):27–33.

    Article  PubMed  Google Scholar 

  • Dos Santos JI, Cardoso FF, Soares AM, Dal Pai Silva M, Gallacci M, Fontes MRM. Structural and functional studies of a bothropic myotoxin complexed to rosmarinic acid: new insights into Lys49-PLA2 inhibition. PLoS ONE. 2011;6(12):e28521.

    Article  PubMed Central  PubMed  Google Scholar 

  • Fortes-Dias CL, Jannotti ML, Franco FJ, Magalhães A, Diniz CR. Studies on the specificity of CNF, a phospholipase A2 inhibitor isolated from the blood plasma of the South American rattlesnake (Crotalus durissus terrificus). I. Interaction with PLA2 from Lachesis muta muta snake venom. Toxicon. 1999;37(12):1747–59.

    Article  CAS  PubMed  Google Scholar 

  • Huancahuire-Vega S, Corrêa DHA, Hollanda LM, Lancellotti M, Ramos CHI, Ponce-Soto LA, et al. Chemical modifications of PhTX-I myotoxin from Porthidium hyoprora snake venom: effects on structural, enzymatic, and pharmacological properties. Biomed Res Int. 2013;2013:103494.

    Article  PubMed Central  PubMed  Google Scholar 

  • Iglesias CV, Aparicio R, Rodrigues-Simioni L, Camargo EA, Antunes E, Marangoni S, et al. Effects of morin on snake venom phospholipase A2 (PLA2). Toxicon. 2005;46(7):751–8.

    Article  CAS  PubMed  Google Scholar 

  • Jain MK, Yu BZ, Rogers JM, Smith AE, Boger ET, Ostrander RL, et al. Specific competitive inhibitor of secreted phospholipase A2 from berries of Schinus terebinthifolius. Phytochemistry. 1995;39(3):537–47.

    Article  CAS  PubMed  Google Scholar 

  • Lima RM, Estevão-Costa MI, Junqueira-de-Azevedo ILM, Ho PL, Diniz MRV, Fortes-Dias CL. Phospholipase A2 inhibitors (βPLIs) are encoded in the venom glands of Lachesis muta (Crotalinae, Viperidae) snakes. Toxicon. 2011;57(1):172–5.

    Article  CAS  PubMed  Google Scholar 

  • Lizano S, Angulo Y, Lomonte B, Fox JW, Lambeau G, Lazdunski M, et al. Two phospholipase A2 inhibitors from the plasma of Cerrophidion (Bothrops) godmani which selectively inhibit two different group-II phospholipase A2 myotoxins from its own venom: isolation, molecular cloning and biological properties. Biochem J. 2000;346(Pt 3):631–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lizano S, Domont G, Perales J. Natural phospholipase A(2) myotoxin inhibitor proteins from snakes, mammals and plants. Toxicon. 2003;42(8):963–77.

    Article  CAS  PubMed  Google Scholar 

  • Lombardo D, Dennis EA. Immobilized phospholipase A2 from cobra venom. Prevention of substrate interfacial and activator effects. J Biol Chem. 1985;260(30):16114–21.

    CAS  PubMed  Google Scholar 

  • Lomonte B, Rangel J. Snake venom Lys49 myotoxins: from phospholipases A(2) to non-enzymatic membrane disruptors. Toxicon. 2012;60(4):520–30.

    Article  CAS  PubMed  Google Scholar 

  • Lomonte B, Gutiérrez JM, Carmona E, Rovira ME. Equine antibodies to Bothrops asper myotoxin II: isolation from polyvalent antivenom and neutralizing ability. Toxicon. 1990;28(4):379–84.

    Article  CAS  PubMed  Google Scholar 

  • Lomonte B, Angulo Y, Calderón L. An overview of lysine-49 phospholipase A2 myotoxins from crotalid snake venoms and their structural determinants of myotoxic action. Toxicon. 2003;42(8):885–901.

    Article  CAS  PubMed  Google Scholar 

  • Lomonte B, León G, Angulo Y, Rucavado A, Núñez V. Neutralization of Bothrops asper venom by antibodies, natural products and synthetic drugs: contributions to understanding snakebite envenomings and their treatment. Toxicon. 2009;54(7):1012–28.

    Article  CAS  PubMed  Google Scholar 

  • Lomonte B, Angulo Y, Moreno E. Synthetic peptides derived from the C-terminal region of Lys49 phospholipase A2 homologues from viperidae snake venoms: biomimetic activities and potential applications. Curr Pharm Des. 2010;16(28):3224–30.

    Article  CAS  PubMed  Google Scholar 

  • Machiah DK, Gowda TV. Purification of a post-synaptic neurotoxic phospholipase A2 from Naja naja venom and its inhibition by a glycoprotein from Withania somnifera. Biochimie. 2006;88(6):701–10.

    Article  CAS  PubMed  Google Scholar 

  • Marchi-Salvador DP, Fernandes CAH, Silveira LB, Soares AM, Fontes MRM. Crystal structure of a phospholipase A(2) homolog complexed with p-bromophenacyl bromide reveals important structural changes associated with the inhibition of myotoxic activity. Biochim Biophys Acta. 2009;1794(11):1583–90.

    Article  CAS  PubMed  Google Scholar 

  • Marcussi S, Sant’Ana CD, Oliveira CZ, Rueda AQ, Menaldo DL, Beleboni RO, et al. Snake venom phospholipase A2 inhibitors: medicinal chemistry and therapeutic potential. Curr Top Med Chem. 2007;7(8):743–56.

    Article  CAS  PubMed  Google Scholar 

  • Murakami MT, Arruda EZ, Melo PA, Martinez AB, Calil-Eliás S, Tomaz MA, et al. Inhibition of myotoxic activity of Bothrops asper myotoxin II by the anti-trypanosomal drug suramin. J Mol Biol. 2005;350(3):416–26.

    Article  CAS  PubMed  Google Scholar 

  • Murari SK, Frey FJ, Frey BM, Gowda TV, Vishwanath BS. Use of Pavo cristatus feather extract for the better management of snakebites: neutralization of inflammatory reactions. J Ethnopharmacol. 2005;99(2):229–37.

    Article  PubMed  Google Scholar 

  • Nataraju A, Raghavendra Gowda CD, Rajesh R, Vishwanath BS. Group IIA secretory PLA2 inhibition by ursolic acid: a potent anti-inflammatory molecule. Curr Top Med Chem. 2007;7(8):801–9.

    Article  CAS  PubMed  Google Scholar 

  • Nazato VS, Rubem-Mauro L, Vieira NAG, dos Santos Rocha-Junior D, Silva MG, Lopes PS, et al. In vitro antiophidian properties of Dipteryx alata Vogel bark extracts. Mol Basel Switz. 2010;15(9):5956–70.

    Article  CAS  Google Scholar 

  • Nirmal N, Praba GO, Velmurugan D. Modeling studies on phospholipase A2-inhibitor complexes. Indian J Biochem Biophys. 2008;45(4):256–62.

    CAS  PubMed  Google Scholar 

  • Nishida M, Okamoto M, Ohno A, Okumura K, Hayashi K, Ikeda K, et al. Inhibitory activities of the heterotrimers formed from two α-type phospholipase A2 inhibitory proteins with different enzyme affinities and importance of the intersubunit electrostatic interaction in trimer formation. Biochim Biophys Acta. 2010;1804(11):2121–7.

    Article  CAS  PubMed  Google Scholar 

  • Nobuhisa I, Inamasu S, Nakai M, Tatsui A, Mimori T, Ogawa T, et al. Characterization and evolution of a gene encoding a Trimeresurus flavoviridis serum protein that inhibits basic phospholipase A2 isozymes in the snake’s venom. Eur J Biochem FEBS. 1997;249(3):838–45.

    Article  CAS  Google Scholar 

  • Nok AJ, Balogun E, Lori JA, Abubakar MS. Inhibition of Naja nigricollis venom acidic phospholipase A2 catalysed hydrolysis of ghost red blood cells by columbin. J Enzym Inhib Med Chem. 2002;17(1):55–9.

    Article  CAS  Google Scholar 

  • Okumura K, Inoue S, Ikeda K, Hayashi K. Identification of beta-type phospholipase A(2) inhibitor in a nonvenomous snake, Elaphe quadrivirgata. Arch Biochem Biophys. 2002;408(1):124–30.

    Article  CAS  PubMed  Google Scholar 

  • Okumura K, Ohno A, Nishida M, Hayashi K, Ikeda K, Inoue S. Mapping the region of the alpha-type phospholipase A2 inhibitor responsible for its inhibitory activity. J Biol Chem. 2005;280(45):37651–9.

    Article  CAS  PubMed  Google Scholar 

  • Oliveira CZ, Menaldo DL, Marcussi S, Santos-Filho NA, Silveira LB, Boldrini-França J, et al. An alpha-type phospholipase A(2) inhibitor from Bothrops jararacussu snake plasma: structural and functional characterization. Biochimie. 2008;90(10):1506–14.

    Article  CAS  PubMed  Google Scholar 

  • Perumal Samy R, Gopalakrishnakone P, Chow VT. Therapeutic application of natural inhibitors against snake venom phospholipase A(2). Bioinformation. 2012;8(1):48–57.

    Article  PubMed Central  PubMed  Google Scholar 

  • Quirós S, Alape-Girón A, Angulo Y, Lomonte B. Isolation, characterization and molecular cloning of AnMIP, a new alpha-type phospholipase A2 myotoxin inhibitor from the plasma of the snake Atropoides nummifer (Viperidae: Crotalinae). Comp Biochem Physiol B Biochem Mol Biol. 2007;146(1):60–8.

    Article  PubMed  Google Scholar 

  • Renetseder R, Brunie S, Dijkstra BW, Drenth J, Sigler PB. A comparison of the crystal structures of phospholipase A2 from bovine pancreas and Crotalus atrox venom. J Biol Chem. 1985;260(21):11627–34.

    CAS  PubMed  Google Scholar 

  • Rocha SLG, Lomonte B, Neves-Ferreira AGC, Trugilho MRO, de Junqueira-de-Azevedo ILM, Ho PL, et al. Functional analysis of DM64, an antimyotoxic protein with immunoglobulin-like structure from Didelphis marsupialis serum. Eur J Biochem FEBS. 2002;269(24):6052–62.

    Article  CAS  Google Scholar 

  • Santos-Filho NA, Silveira LB, Oliveira CZ, Bernardes CP, Menaldo DL, Fuly AL, et al. A new acidic myotoxic, anti-platelet and prostaglandin I2 inductor phospholipase A2 isolated from Bothrops moojeni snake venom. Toxicon. 2008;52(8):908–17.

    Article  CAS  PubMed  Google Scholar 

  • Santos-Filho NA, Fernandes CAH, Menaldo DL, Magro AJ, Fortes-Dias CL, Estevão-Costa MI, et al. Molecular cloning and biochemical characterization of a myotoxin inhibitor from Bothrops alternatus snake plasma. Biochimie. 2011;93(3):583–92.

    Article  CAS  PubMed  Google Scholar 

  • Schaloske RH, Dennis EA. The phospholipase A2 superfamily and its group numbering system. Biochim Biophys Acta. 2006;1761(11):1246–59.

    Article  CAS  PubMed  Google Scholar 

  • Shimabuku PS, Fernandes CAH, Magro AJ, Costa TR, Soares AM, Fontes MRM. Crystallization and preliminary X-ray diffraction analysis of a Lys49-phospholipase A2 complexed with caffeic acid, a molecule with inhibitory properties against snake venoms. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2011;67(Pt 2):249–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shirai R, Toriba M, Hayashi K, Ikeda K, Inoue S. Identification and characterization of phospholipase A2 inhibitors from the serum of the Japanese rat snake, Elaphe climacophora. Toxicon. 2009;53(6):685–92.

    Article  CAS  PubMed  Google Scholar 

  • Soares AM, Giglio JR. Chemical modifications of phospholipases A2 from snake venoms: effects on catalytic and pharmacological properties. Toxicon. 2003;42(8):855–68.

    Article  CAS  PubMed  Google Scholar 

  • Strauch MA, Tomaz MA, Monteiro-Machado M, Ricardo HD, Cons BL, Fernandes FFA, et al. Antiophidic activity of the extract of the Amazon plant Humirianthera ampla and constituents. J Ethnopharmacol. 2013;145(1):50–8.

    Article  CAS  PubMed  Google Scholar 

  • Thwin MM, Gopalakrishnakone P, Kini RM, Armugam A, Jeyaseelan K. Recombinant antitoxic and antiinflammatory factor from the nonvenomous snake Python reticulatus: phospholipase A2 inhibition and venom neutralizing potential. Biochemistry (Mosc). 2000;39(31):9604–11.

    Article  CAS  Google Scholar 

  • Thwin M-M, Samy RP, Satyanarayanajois SD, Gopalakrishnakone P. Venom neutralization by purified bioactive molecules: synthetic peptide derivatives of the endogenous PLA(2) inhibitory protein PIP (a mini-review). Toxicon. 2010;56(7):1275–83.

    Article  CAS  PubMed  Google Scholar 

  • Toyama DO, Marangoni S, Diz-Filho EBS, Oliveira SCB, Toyama MH. Effect of umbelliferone (7-hydroxycoumarin, 7-HOC) on the enzymatic, edematogenic and necrotic activities of secretory phospholipase A2 (sPLA2) isolated from Crotalus durissus collilineatus venom. Toxicon. 2009;53(4):417–26.

    Article  CAS  PubMed  Google Scholar 

  • Vale LHF, Mendes MM, Fernandes RS, Costa TR, Hage-Melim LIS, Sousa MA, et al. Protective effect of schizolobium parahyba flavonoids against snake venoms and isolated toxins. Curr Top Med Chem. 2011;11(20):2566–77.

    Article  CAS  Google Scholar 

  • Vishwanath BS, Gowda TV. Interaction of aristolochic acid with Vipera russelli phospholipase A2: its effect on enzymatic and pathological activities. Toxicon. 1987;25(9):929–37.

    Article  CAS  PubMed  Google Scholar 

  • Ximenes RM, Alves RS, Pereira TP, Araújo RM, Silveira ER, Rabello MM, et al. Harpalycin 2 inhibits the enzymatic and platelet aggregation activities of PrTX-III, a D49 phospholipase A2 from Bothrops pirajai venom. BMC Complement Altern Med. 2012;12:139.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Instituto de Química de Araraquara, Universidade Estadual Paulista Júlio de Mesquita Filho – UNESP, Rua Prof. Francisco Degni, 55, 14800-900, Araraquara, São Paulo, Brazil

    Norival Alves Santos-Filho

  2. Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo – FCFRP-USP, 05508-070, Ribeirão Preto, São Paulo, Brazil

    Lucas Blundi Silveira

  3. Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo – FCFRP-USP, 05508-070, Ribeirão Preto, São Paulo, Brazil

    Johara Boldrini-França

Authors
  1. Norival Alves Santos-Filho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lucas Blundi Silveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Johara Boldrini-França
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Norival Alves Santos-Filho .

Editor information

Editors and Affiliations

  1. Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    P. Gopalakrishnakone

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media Dordrecht

About this entry

Cite this entry

Santos-Filho, N.A., Silveira, L.B., Boldrini-França, J. (2015). Myotoxin Inhibitors. In: Gopalakrishnakone, P. (eds) Toxins and Drug Discovery. Toxinology. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6726-3_12-1

Download citation

  • DOI: https://doi.org/10.1007/978-94-007-6726-3_12-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Dordrecht

  • Online ISBN: 978-94-007-6726-3

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation