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Purification and characterization of peptides present in the venom of African snakes: searching for peptidase inhibitor of medical importance

Grant number: 15/13124-5
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): October 01, 2015
Effective date (End): August 31, 2019
Field of knowledge:Biological Sciences - Biochemistry - Enzymology
Principal Investigator:Fernanda Calheta Vieira Portaro
Grantee:Roberto Tadashi Kodama
Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil


Peptidases are essential for the proper physiological activities of the various organisms, from protozoa to large mammals. However, a deregulation of these activities may be the cause of severe pathologies. One of these is calpain, a cysteine peptidase which is found in a seven-time higher concentration in animals that have developed Alzheimer disease, when compared to normal animals. Another example is the case of the deregulation of elastase, and, when it presents excessive activity, this serine peptidase can induce chronic obstructive pulmonary disease, leading to severe lung inflammation. Animal venoms are a complex mixture of different types of molecules, and the presence of peptides in the venom of snakes that regulate peptidase's activity has been already demonstrated. This is the case of bradykinin potentiating peptide (BPP), firstly found in the Bothrops jararaca venom and further in other venomous species, such as the African Bitis spp. It was a BPP - a peptide responsible for the inhibition of angiotensin I converting enzyme (ACE) - that inspired the design of captopril, a potent drug used for the treatment of patients diagnosed with hypotension. Another case is the Kunitz type serine peptidase inhibitor that was isolated from the venom of Macrovipera lebetina transmediterranea, that possess anti-tumoral effects. Is noteworthy to mention that cysteine peptidases inhibitors were found in Naja spp and Bitis arietans venoms. During the Master Project, we had the opportunity to work with the low molecular mass portion of the venom of four snakes from the Bitis genus, and peptides capable of inhibiting the ACE activity and promote hypotension in in vivo experiments were purified and characterized. To verify the probable success of this PhD project, we used some of the fractions partially purified during the Master's project to investigate if these fractions could inhibit the elastase activity. The results showed that four fractions had an inhibition rate higher than 70% of the elastase activity, indicating that these venoms potentially have serine peptidase inhibitors. We also investigated the inhibition of the low molecular mass portion of the venoms of Bitis spp, Naja mossambica and Dendoraspis polylepis on the activity of papain, a cysteine peptidase similar to cathepsin L, and, so far, the results have been rather promising. Taking all this into account, we compellingly intend to extend the studies in the low molecular mass portion of these African snake venoms, aiming to purify and characterize the inhibitors of serine, metallo, and cysteine peptidases, all of them of recognized of medical importance. The new to-be-found inhibitors will be sequenced by mass spectrometry and synthesized. The synthetic inhibitors will be tested using the above described peptidases and the inhibition mechanism and constant will be determined. In silico molecular modeling and anchorage of the inhibitors of interest in their respective targets (catalytic sites of peptidase) will also be carried out to evaluate the complementarity between them, allowing us to understand and elucidate the molecular interactions that contributed to the actions of the compounds, and also providing subsidies for the planning of potential new inhibitors. (AU)

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Scientific publications (5)
(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)
ALBERTO-SILVA, CARLOS; VIEIRA PORTARO, FERNANDA CALHETA; KODAMA, ROBERTO TADASHI; PANTALEAO, HALYNE QUEIROZ; INAGAKI, HIDETOSHI; NIHEI, KEN-ICHI; KONNO, KATSUHIRO. Comprehensive Analysis and Biological Characterization of Venom Components from Solitary Scoliid Wasp Campsomeriella annulata annulata. TOXINS, v. 13, n. 12, . (19/20832-7, 15/13124-5)
DUZZI, BRUNO; FERNANDES SILVA, CRISTIANE CASTILHO; KODAMA, ROBERTO TADASHI; CAJADO-CARVALHO, DANIELA; SQUAIELLA-BAPTISTAO, CARLA CRISTINA; VIEIRA PORTARO, FERNANDA CALHETA. New Insights into the Hypotensins from Tityus serrulatus Venom: Pro-Inflammatory and Vasopeptidases Modulation Activities. TOXINS, v. 13, n. 12, p. 13-pg., . (19/20832-7, 14/12976-5, 15/13124-5, 13/15343-0)
KUNIYOSHI, ALEXANDRE KAZUO; KODAMA, ROBERTO TADASHI; CAJADO-CARVALHO, DANIELA; IWAI, LEO KEI; KITANO, EDUARDO; FERNANDES DA SILVA, CRISTIANE CASTILHO; DUZZI, BRUNO; DA SILVA, WILMAR DIAS; PORTARO, FERNANDA CALHETA. Experimental antivenom against serine proteases from the Bothrops jararaca venom obtained in mice, and its comparison with the antibothropic serum from the Butantan Institute. Toxicon, v. 169, p. 59-67, . (15/13124-5, 13/07467-1, 13/15344-7, 12/06677-0, 15/15364-3)
KUNIYOSHI, ALEXANDRE KAZUO; KODAMA, ROBERTO TADASHI; FERREIRA MORAES, LUIS HENRIQUE; DUZZI, BRUNO; IWAI, LEO KEI; LIMA, ISMAEL FEITOSA; CAJADO-CARVALHO, DANIELA; PORTARO, FERNANDA VIEIRA. In vitro cleavage of bioactive peptides by peptidases from Bothrops jararaca venom and its neutralization by bothropic antivenom produced by Butantan Institute: Major contribution of serine peptidases. Toxicon, v. 137, p. 114-119, . (13/07467-1, 15/13124-5, 12/06677-0, 15/15364-3, 13/15344-7)
ROBERTO TADASHI KODAMA; ALEXANDRE KAZUO KUNIYOSHI; CRISTIANE CASTILHO FERNANDES DA SILVA; DANIELA CAJADO-CARVALHO; BRUNO DUZZI; DOUGLAS CEOLIN MARIANO; DANIEL C. PIMENTA; RAFAEL BORGES; WILMAR DIAS DA SILVA; FERNANDA CALHETA VIEIRA PORTARO. A Kunitz-type peptide from Dendroaspis polylepis venom as a simultaneous inhibitor of serine and cysteine proteases. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 26, . (15/15364-3, 13/15344-7, 13/07467-1, 11/02061-1, 15/13124-5)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
KODAMA, Roberto Tadashi. Purification and characterization of peptides present in African snake venoms: searching for inhibitors of medical importance peptidases. 2019. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.

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