The dinoponeratoxin peptides from the giant ant Dinoponera quadriceps display in vitro antitrypanosomal activity
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Dânya Bandeira Lima
und
Alice Maria Costa Martins
Abstract
The crude venom of the giant ant Dinoponera quadriceps is a cocktail of polypeptides and organic compounds that shows antiparasitic effects against Trypanosoma cruzi, the causative agent of Chagas disease. In order to investigate the venom-derived components responsible for such antitrypanosomal activity, four dinoponeratoxins (DnTxs) were identified, namely M-PONTX-Dq3a, -Dq3b, -Dq3c and -Dq4e, that are diverse in size, net charge, hydrophobicity and propensity to interact with eukaryote cell membranes. These peptides were tested against epimastigote, trypomastigote and amastigote forms of benznidazole (Bz)-resistant Y strain of T. cruzi and in mammalian host cells. The M-PONTX-Dq3a and -Dq4e inhibited all developmental forms of T. cruzi, including amastigotes, the responsible form for the maintenance of infection on chronic phase of the disease. The M-PONTX-Dq3a showed the highest selectivity index (SI) (80) and caused morphological alterations in T. cruzi, as observed by scanning electron microscopy (SEM), and induced cell death through necrosis, as seen by multiparametric flow cytometry analysis with specific biochemical markers. Altogether, the D. quadriceps venom appears as a source for the prospection of trypanocidal peptides and the M-PONTX-Dq3a arises as a candidate among the dinoponeratoxin-related peptides in the development of compounds against Chagas disease.
Acknowledgments
The authors are grateful for the funding agencies, the Brazilian National Council for Scientific and Technological Development (CNPq), the Ministry of Science, Technology and Innovation (MCTI) and the Coordination for the Improvement of Higher Education Personnel (CAPES), the Ministry of Education and Culture, both of the Federal Government of Brazil, for the financial support of the project development and the fellowships of graduate students, respectively. We are also thankful to the Analytical Center Core Facility of the Federal University of Ceará for the technical support on Electron Microscopy studies. Our deepest thanks to Professor Katsuhiro Konno, Institute of Natural Medicine, University of Toyama, Toyama, Japan, and Dr. André J. Zaharenko and Dr. Álvaro Rossan B. Prieto-da-Silva, Laboratory of Genetics, Institute Butantan, São Paulo, Brazil, for the preliminary proteomic and peptidome analysis of D. quadriceps crude venom.
Conflict of interest statement: Authors declare no conflict of interest.
References
Adade, C.M., Oliveira, I.R., Pais, J.A., and Souto-Padron, T. (2013). Melittin peptide kills Trypanosoma cruzi parasites by inducing different cell death pathways. Toxicon 69, 227–239.10.1016/j.toxicon.2013.03.011Suche in Google Scholar PubMed
Adade, C.M., Carvalho, A.L., Tomaz, M.A., Costa, T.F., Godinho, J.L., Melo, P.A., Lima, A.P., Rodrigues, J.C., Zingali, R.B., and Souto-Padron, T. (2014). Crovirin, a snake venom cysteine-rich secretory protein (CRISP) with promising activity against trypanosomes and Leishmania. PLoS Negl. Trop. Dis. 8, e3252.10.1371/journal.pntd.0003252Suche in Google Scholar PubMed PubMed Central
Andrews, N.W. and Colli, W. (1982). Adhesion and interiorization of Trypanosoma cruzi in mammalian cells. J. Protozool. 29, 264–269.10.1111/j.1550-7408.1982.tb04024.xSuche in Google Scholar PubMed
Chatelain, E. (2017). Chagas disease research and development: is there light at the end of the tunnel? Comput. Struct. Biotechnol. J. 15, 98–103.10.1016/j.csbj.2016.12.002Suche in Google Scholar PubMed PubMed Central
Cologna, C.T., Cardoso Jdos, S., Jourdan, E., Degueldre, M., Upert, G., Gilles, N., Uetanabaro, A.P., Costa Neto, E.M., Thonart, P., de Pauw, E., et al. (2013). Peptidomic comparison and characterization of the major components of the venom of the giant ant Dinoponera quadriceps collected in four different areas of Brazil. J. Proteomics 94, 413–422.10.1016/j.jprot.2013.10.017Suche in Google Scholar PubMed
de Souza, W., de Carvalho, T.M., and Barrias, E.S. (2010). Review on Trypanosoma cruzi: host cell interaction. Int. J. Cell Biol. 2010. PMID: 20811486. Doi: 10.1155/2010/295394.10.1155/2010/295394Suche in Google Scholar PubMed PubMed Central
Eisenberg, D., Weiss, R.M., and Terwilliger, T.C. (1982). The helical hydrophobic moment: a measure of the amphiphilicity of a helix. Nature 299, 371–374.10.1038/299371a0Suche in Google Scholar PubMed
Falcao, C.B., de La Torre, B.G., Perez-Peinado, C., Barron, A.E., Andreu, D., and Radis-Baptista, G. (2014). Vipericidins: a novel family of cathelicidin-related peptides from the venom gland of South American pit vipers. Amino Acids 46, 2561–2571.10.1007/s00726-014-1801-4Suche in Google Scholar PubMed
Falcao, C.B., Perez-Peinado, C., de la Torre, B.G., Mayol, X., Zamora-Carreras, H., Jimenez, M.A., Radis-Baptista, G., and Andreu, D. (2015). Structural dissection of crotalicidin, a rattlesnake venom cathelicidin, retrieves a fragment with antimicrobial and antitumor activity. J. Med. Chem. 58, 8553–8563.10.1021/acs.jmedchem.5b01142Suche in Google Scholar PubMed
Harvey, A.L. (2014). Toxins and drug discovery. Toxicon 92, 193–200.10.1016/j.toxicon.2014.10.020Suche in Google Scholar PubMed
Johnson, S.R., Copello, J.A., Evans, M.S. and Suarez, A.V. (2010). A biochemical characterization of the major peptides from the venom of the giant neotropical hunting ant Dinoponera australis. Toxicon 55, 702–710.10.1016/j.toxicon.2009.10.021Suche in Google Scholar PubMed
Lima, D.B., Torres, A.F., Mello, C.P., de Menezes, R.R., Sampaio, T.L., Canuto, J.A., da Silva, J.J., Freire, V.N., Quinet, Y.P., Havt, A., et al. (2014). Antimicrobial effect of Dinoponera quadriceps (Hymenoptera: Formicidae) venom against Staphylococcus aureus strains. J. Appl. Microbiol. 117, 390–396.10.1111/jam.12548Suche in Google Scholar PubMed
Lima, D.B., Sousa, P.L., Torres, A.F., Rodrigues, K.A., Mello, C.P., Menezes, R.R., Tessarolo, L.D., Quinet, Y.P., de Oliveira, M.R., and Martins, A.M. (2016). Antiparasitic effect of Dinoponera quadriceps giant ant venom. Toxicon 120, 128–132.10.1016/j.toxicon.2016.08.008Suche in Google Scholar PubMed
Mello, C.P., Lima, D.B., Menezes, R.R., Bandeira, I.C., Tessarolo, L.D., Sampaio, T.L., Falcao, C.B., Radis-Baptista, G., and Martins, A.M. (2017). Evaluation of the antichagasic activity of batroxicidin, a cathelicidin-related antimicrobial peptide found in Bothrops atrox venom gland. Toxicon 130, 56–62.10.1016/j.toxicon.2017.02.031Suche in Google Scholar PubMed
Morilla, M.J. and Romero, E.L. (2015). Nanomedicines against Chagas disease: an update on therapeutics, prophylaxis and diagnosis. Nanomedicine (Lond.) 10, 465–481.10.2217/nnm.14.185Suche in Google Scholar PubMed
Nwaka, S. and Hudson, A. (2006). Innovative lead discovery strategies for tropical diseases. Nat. Rev. Drug Discov. 5, 941–955.10.1038/nrd2144Suche in Google Scholar PubMed
Papo, N., Oren, Z., Pag, U., Sahl, H.G., and Shai, Y. (2002). The consequence of sequence alteration of an amphipathic alpha-helical antimicrobial peptide and its diastereomers. J. Biol. Chem. 277, 33913–33921.10.1074/jbc.M204928200Suche in Google Scholar PubMed
Rodrigues, J.H., Ueda-Nakamura, T., Correa, A.G., Sangi, D.P., and Nakamura, C.V. (2014). A quinoxaline derivative as a potent chemotherapeutic agent, alone or in combination with benznidazole, against Trypanosoma cruzi. PLoS One 9, e85706.10.1371/journal.pone.0085706Suche in Google Scholar PubMed PubMed Central
Souza, A.L., Faria, R.X., Calabrese, K.S., Hardoim, D.J., Taniwaki, N., Alves, L.A., and De Simone, S.G. (2016). Temporizin and Temporizin-1 peptides as novel candidates for eliminating Trypanosoma cruzi. PLoS One 11, e0157673.10.1371/journal.pone.0157673Suche in Google Scholar PubMed PubMed Central
Torres, A.F., Huang, C., Chong, C.M., Leung, S.W., Prieto-da-Silva, A.R., Havt, A., Quinet, Y.P., Martins, A.M., Lee, S.M., and Radis-Baptista, G. (2014). Transcriptome analysis in venom gland of the predatory giant ant Dinoponera quadriceps: insights into the polypeptide toxin arsenal of hymenopterans. PLoS One 9, e87556.10.1371/journal.pone.0087556Suche in Google Scholar PubMed PubMed Central
Touchard, A., Aili, S.R., Fox, E.G., Escoubas, P., Orivel, J., Nicholson, G.M., and Dejean, A. (2016). The Biochemical toxin arsenal from ant venoms. Toxins (Basel) 8, 30.10.3390/toxins8010030Suche in Google Scholar PubMed PubMed Central
Urbina, J.A. and Docampo, R. (2003). Specific chemotherapy of Chagas disease: controversies and advances. Trends Parasitol. 19, 495–501.10.1016/j.pt.2003.09.001Suche in Google Scholar PubMed
Vanden Berghe, T., Grootjans, S., Goossens, V., Dondelinger, Y., Krysko, D.V., Takahashi, N., and Vandenabeele, P. (2013). Determination of apoptotic and necrotic cell death in vitro and in vivo. Methods 61, 117–129.10.1016/j.ymeth.2013.02.011Suche in Google Scholar PubMed
WHO. (2017). Chagas disease (American trypanosomiasis). Geneva, Switzerland: World Health Organization Media Centre. No 340.Suche in Google Scholar
Yacoub, H.A., Elazzazy, A.M., Mahmoud, M.M., Baeshen, M.N., Al-Maghrabi, O.A., Alkarim, S., Ahmed, E.S., Almehdar, H.A., and Uversky, V.N. (2016). Chicken cathelicidins as potent intrinsically disordered biocides with antimicrobial activity against infectious pathogens. Dev. Comp. Immunol. 65, 8–24.10.1016/j.dci.2016.06.012Suche in Google Scholar PubMed
Zingales, B., Pereira, M.E., Almeida, K.A., Umezawa, E.S., Nehme, N.S., Oliveira, R.P., Macedo, A., and Souto, R.P. (1997). Biological parameters and molecular markers of clone CL Brener – the reference organism of the Trypanosoma cruzi genome project. Mem Inst. Oswaldo Cruz 92, 811–814.10.1590/S0074-02761997000600016Suche in Google Scholar PubMed
Supplemental Material:
The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2017-0198).
©2018 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Review
- Structure and function of the human parvulins Pin1 and Par14/17
- Structural mechanisms of HECT-type ubiquitin ligases
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- Minireview
- PARP-1 and PARP-2 activity in cancer-induced cachexia: potential therapeutic implications
- Research Articles/Short Communications
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Artikel in diesem Heft
- Frontmatter
- Review
- Structure and function of the human parvulins Pin1 and Par14/17
- Structural mechanisms of HECT-type ubiquitin ligases
- Mechanisms, pathophysiological roles and methods for analyzing mitophagy – recent insights
- Minireview
- PARP-1 and PARP-2 activity in cancer-induced cachexia: potential therapeutic implications
- Research Articles/Short Communications
- Protein Structure and Function
- The dinoponeratoxin peptides from the giant ant Dinoponera quadriceps display in vitro antitrypanosomal activity
- The inhibition of the mitochondrial F1FO-ATPase activity when activated by Ca2+ opens new regulatory roles for NAD+
