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Searching for lead compounds for rational development of new drugs and pesticides through bioprospecting in Brazilian arthropods

Grant number: 06/57122-7
Support type:BIOTA-FAPESP Program - Thematic Grants
Duration: December 01, 2007 - November 30, 2011
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Principal Investigator:Mario Sergio Palma
Grantee:Mario Sergio Palma
Home Institution: Instituto de Biociências (IB). Universidade Estadual Paulista (UNESP). Campus de Rio Claro. Rio Claro , SP, Brazil
Associated scholarship(s):10/19051-6 - Structural analysis of silk proteins of Nephila clavipes spider web by a proteomic approach, BP.DR
10/11823-0 - Mechanisms of interactions of lipid bilayers and amphiphilic substances of therapeutic interest, BP.PD
10/00747-0 - Differential patterns in exposure at thiamethoxam and the seasonal variation of the enzymatic activity of Apis mellifera: potential as indicator in the environmental quality, BP.PD
+ associated scholarships 09/06701-5 - Morphologic and IMUNOCITOQUÍMICA analysis of the brain from larvae bee Africanized of Apis mellifera after exposure to low dose of TIAMETOXAN, BP.MS
09/11155-0 - The use of LC-ESI-IT-Tof/MS and MSn system for prospecting new peptides from the venom of the social wasp Polybia paulista, BP.MS
09/15798-2 - Comparative analysis of the low molecular mass compounds secretome from the venom of social wasps by "footprinting" approach, BP.PD
09/02168-0 - Study of structure-function relationship of semi-cyclical peptides: a novel class toxin of the venom of social wasps, BP.PD
09/05342-1 - Influence of pyriproxyfen on the differentiation and development of the flight muscles of workers of Apis mellifera (Hymenoptera: Apidae), BP.PD
08/09624-9 - Nociceptive and antinociceptive studies of isolated peptides from neotropicals insects of São Paulo State, BP.PD
08/05018-7 - Toxicological effects of the insecticide fipronil in workers and queens of Apis mellifera (Hymenoptera: Apidae): neural activity and detoxification proteins, BP.PD
08/03929-2 - Evaluation of the effects of imidacloprid, on the nervous system of Africanized Apis mellifera, through the Expression of Fos protein, BP.IC
07/07928-8 - Prospecting mastoparan-membrane interaction in proteolipossomes as models for the rational development of novel antimicrobial agents, BP.MS - associated scholarships


Many modem medicines currently prescribed were initially discovered in the nature. Despite the progresses in chemistry and in the development of sophisticated instruments used in the combinatorial synthesis of novel compounds, the scientists are still using the nature as source of inspiration for the development of novel drugs. A substantial fraction of medicines under therapeutical use nowadays was directly or indirectly derived from bioactive natural compounds from plants and microorganisms. Recently, the low molecular masses compounds from animal origin have been subject of interest of pharmaceutical and agrichemical companies. The Arthropods are considered a source of potentially important of novel molecules, which offer notable properties such as: high efficiency, low probability of development of microbial resistance, limited toxicity and low immunogenicity to the men. Some Arthropods produce toxins which may present unique actions in nervous systems and could become useful tools in neurobiology investigations; the knowledge about mechanisms of action of these toxins certainly will open new perspectives in the therapeutic area and in the development of specific bioinsecticides. In addition to the defensive used of low molecular masses compounds, the spider also use these toxins to paralyze and/or to kill their preys, affecting the synaptic transmissions and blocking directly ion channels and/or their associated receptors. Polycationic peptides constitute important toxins in the toxic secretions of from the social Hymenoptera, presenting antibiotic, anti-inflammatory, anti-hypertensive and even analgesic effects, representing interesting model of compounds for the development of novel drugs for therapeutical uses. In order to bioprospect such types of compounds in the Arthropod fauna from São Paulo State, the main objectives of the present project are: To identify the most abundant low molecular masses compounds from the toxic secretions of spiders and social Hymenoptera presenting neuroactive actions; to elucidate their molecular structures, to synthesize and to submit them to pharmacological and physiological bioassay screenings. As auxiliary tool in this type of investigation we intend to implement a platform of metabolome analysis; Also the polycationic peptides will be investigated; their primary sequences will be determined, their secondary structure will be studied and their tridimensional structure will be assigned; for some of these components their target-receptors will identified. The elucidation of chemical structures in general will be performed by using a series of spectroscopic techniques, such as: MS, MS/MS, HRMS, 1H- and 13C-RMN, FT-IR, C, X-Ray, among other techniques. In the case of peptides Degradative Chemistry of Edman also will be used to sequence them. When necessary the elucidated chemical structures will be synthesized and used for functional characterization. The biological characterization of the neuroactive compounds, will include the classical neuropharmacology approach, immunohistochemistry and electrophysiology methods. The investigation of the mechanism of action of the polycationic peptides will focus traditional protocols of pharmacology for pain, analgesy and inflammation; the investigation of the antibiotic action of these peptides will consider strategies for the investigations of their interaction with membrane-mimetic systems, spectrofluorimetry, fluorescence microscopy techniques, mass spectrometry associated to HID exchange, molecular modeling of peptides and molecular dynamics. From the point of view of human resources this project also will deal with the high qualification of young researchers in: structural elucidations of low molecular masses compounds and peptides through the use of spectroscopic approaches, organic synthesis and setting-up of pharmacologicall physiological bioassay screening protocols. The promising compounds, presenting some specific potential application at level of therapeutic use, which may be used as models for future drug development, will be submitted to a an intensive investigation about structure/activity relationship for a future rational development of novel drugs. (AU)

Articles published in Agência FAPESP about the research grant
Scientists examine venoms in search of new drugs  

Scientific publications (17)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
RODRIGUES GUERRA, MIRIAN ELISA; FADEL, VALMIR; MALTAROLLO, VINICIUS GONCALVES; BALDISSERA, GISELE; HONORIO, KATHIA MARIA; RUGGIERO, JOSE ROBERTO; DOS SANTOS CABRERA, MARCIA PEREZ. MD simulations and multivariate studies for modeling the antileishmanial activity of peptides. CHEMICAL BIOLOGY & DRUG DESIGN, v. 90, n. 4, p. 501-510, OCT 2017. Web of Science Citations: 3.
BALDISSERA, GISELE; DOS SANTOS CABRERA, MARCIA PEREZ; CHAHINE, JORGE; RUGGIERO, JOSE ROBERTO. Role of Peptide Peptide Interactions in Aggregation: Protonectins Observed in Equilibrium and Replica Exchange Molecular Dynamics Simulations. BIOCHEMISTRY, v. 54, n. 13, p. 2262-2269, APR 7 2015. Web of Science Citations: 2.
DOS SANTOS CABRERA, MARCIA PEREZ; BALDISSERA, GISELE; SILVA-GONCALVES, LAIZ DA COSTA; DE SOUZA, BIBIANA MONSON; RISKE, KARIN A.; PALMA, MARIO SERGIO; RUGGIERO, JOSE ROBERTO; ARCISIO-MIRANDA, MANOEL. Combining Experimental Evidence and Molecular Dynamic Simulations To Understand the Mechanism of Action of the Antimicrobial Octapeptide Jelleine-I. BIOCHEMISTRY, v. 53, n. 29, p. 4857-4868, JUL 29 2014. Web of Science Citations: 8.
ROSSI, CAROLINE DE ALMEIDA; ROAT, THAISA CRISTINA; TAVARES, DAIANA ANTONIA; CINTRA-SOCOLOWSKI, PRISCILA; MALASPINA, OSMAR. Brain Morphophysiology of Africanized Bee Apis mellifera Exposed to Sublethal Doses of Imidacloprid. Archives of Environmental Contamination and Toxicology, v. 65, n. 2, p. 234-243, AUG 2013. Web of Science Citations: 18.
ROSSI, CAROLINE DE ALMEIDA; ROAT, THAISA CRISTINA; TAVARES, DAIANA ANTONIA; CINTRA-SOCOLOWSKI, PRISCILA; MALASPINA, OSMAR. Effects of sublethal doses of imidacloprid in malpighian tubules of africanized Apis mellifera (Hymenoptera, Apidae). MICROSCOPY RESEARCH AND TECHNIQUE, v. 76, n. 5, p. 552-558, MAY 2013. Web of Science Citations: 27.
DOS SANTOS CABRERA, MARCIA PEREZ; ARCISIO-MIRANDA, MANOEL; GORJAO, RENATA; LEITE, NATALIA BUENO; DE SOUZA, BIBIANA MONSON; CURI, RUI; PROCOPIO, JOAQUIM; RUGGIERO NETO, JOAO; PALMA, MARIO SERGIO. Influence of the Bilayer Composition on the Binding and Membrane Disrupting Effect of Polybia-MP1, an Antimicrobial Mastoparan Peptide with Leukemic T-Lymphocyte Cell Selectivity. BIOCHEMISTRY, v. 51, n. 24, p. 4898-4908, JUN 19 2012. Web of Science Citations: 18.
BAPTISTA-SAIDEMBERG, NICOLI BARAO; SAIDEMBERG, DANIEL MENEZES; PALMA, MARIO SERGIO. Profiling the peptidome of the venom from the social wasp Agelaia pallipes pallipes. JOURNAL OF PROTEOMICS, v. 74, n. 10, p. 2123-2137, SEP 6 2011. Web of Science Citations: 20.
DOS SANTOS CABRERA, MARCIA P.; ALVARES, DAYANE S.; LEITE, NATALIA B.; DE SOUZA, BIBIANA MONSON; PALMA, MARIO S.; RISKE, KARIN A.; NETO, JOAO RUGGIERO. New Insight into the Mechanism of Action of Wasp Mastoparan Peptides: Lytic Activity and Clustering Observed with Giant Vesicles. Langmuir, v. 27, n. 17, p. 10805-10813, SEP 6 2011. Web of Science Citations: 34.
VASO, ALESSANDRA; DOS SANTOS, DIOGENES S.; BASSO, LUIS AUGUSTO; PALMA, MARIO S. Hydrogen/deuterium exchange mass spectrometry for characterizing phosphoenolpyruvate-induced structural transitions in Mycobacterium tuberculosis 5-enolpyruvylshikimate-3-phosphate synthase (EC INTERNATIONAL JOURNAL OF MASS SPECTROMETRY, v. 302, n. 1-3, SI, p. 12-18, APR 30 2011. Web of Science Citations: 1.
DOS SANTOS, LUCILENE DELAZARI; DA SILVA MENEGASSO, ANALLY RIBEIRO; APARECIDO DOS SANTOS PINTO, JOSE ROBERTO; SANTOS, KEITY SOUZA; CASTRO, FABIO MORATO; KALIL, JORGE ELIAS; PALMA, MARIO SERGIO. Proteomic characterization of the multiple forms of the PLAs from the venom of the social wasp Polybia paulista. PROTEOMICS, v. 11, n. 8, p. 1403-1412, APR 2011. Web of Science Citations: 26.
ARCURI, H. A.; PALMA, M. S. Understanding the Structure, Activity and Inhibition of Chorismate Synthase from Mycobacterium tuberculosis. Current Medicinal Chemistry, v. 18, n. 9, p. 1311-1317, MAR 2011. Web of Science Citations: 7.
SAIDEMBERG, D. M.; PASSARELLI, A. W.; RODRIGUES, A. V.; BASSO, L. A.; SANTOS, D. S.; PALMA, M. S. Shikimate Kinase (EC from Mycobacterium tuberculosis: Kinetics and Structural Dynamics of a Potential Molecular Target for Drug Development. Current Medicinal Chemistry, v. 18, n. 9, p. 1299-1310, MAR 2011. Web of Science Citations: 4.
CESAR-TOGNOLI, LILIAN M. M.; SALAMONI, SIMONE D.; TAVARES, ANDREA A.; ELIAS, CAROL F.; DA COSTA, JADERSON C.; BITTENCOURT, JACKSON C.; PALMA, MARIO S. Effects of Spider Venom Toxin PWTX-I (6-Hydroxytrypargine) on the Central Nervous System of Rats. TOXINS, v. 3, n. 2, p. 142-162, FEB 2011. Web of Science Citations: 5.
SANTOS, L. D.; PIERONI, M.; MENEGASSO, A. R. S.; PINTO, J. R. A. S.; PALMA, M. S. A new scenario of bioprospecting of Hymenoptera venoms through proteomic approach. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 17, n. 4, p. 364-377, 2011. Web of Science Citations: 22.
SAIDEMBERG, DANIEL M.; FERREIRA, MARCO A. B.; TAKAHASHI, TATIANE N.; GOMES, PAULO C.; CESAR-TOGNOLI, LILIAN M. M.; DA SILVA-FILHO, LUIZ C.; TORMENA, CLAUDIO F.; DA SILVA, GIL V. J.; PALMA, MARIO S. Monoamine oxidase inhibitory activities of indolylalkaloid toxins from the venom of the colonial spider Parawixia bistriata: Functional characterization of PwTX-I. Toxicon, v. 54, n. 6, p. 717-724, NOV 2009. Web of Science Citations: 15.
DOS SANTOS CABRERA, MARCIA PEREZ; ARCISIO-MIRANDA, MANOEL; DA COSTA, LAIANA CRISTINA; DE SOUZA, BIBIANA MONSON; BROGGIO COSTA, SABRINA THAIS; PALMA, MARIO SERGIO; RUGGIERO NETO, JOAO; PROCOPIO, JOAQUIM. Interactions of mast cell degranulating peptides with model membranes: A comparative biophysical study. Archives of Biochemistry and Biophysics, v. 486, n. 1, p. 1-11, JUN 1 2009. Web of Science Citations: 21.

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