Synthesis of peptidic inhibitors: a strategy for improvement of the antibothrops serum produced by the Butantan Institute

• Grant number: 17/04321-7
• Support Opportunities: Regular Research Grants
• Duration: July 01, 2017 - June 30, 2019
• Field of knowledge: Health Sciences - Collective Health - Public Health
• Principal Investigator: Sonia Aparecida de Andrade Chudzinski
• Grantee: Sonia Aparecida de Andrade Chudzinski
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated researchers: Fernanda Calheta Vieira Portaro ; Francisco Humberto de Abreu Maffei ; Montserrat Heras Corominas

Abstract

Snake envenomation is an important public health problem in Brazil and in other countries due to its frequency and severity. Some studies have shown that every year there are around 5.4 - 5.5 million accidents which result in more than 400.000 amputations and from 20.000 to 125.000 deaths in whole world. Bothrops envenomations are responsible for 90% of snake bites in Brazil and for the patients treated in Vital Brazil Hospital (Butantan Institute) this percentage comes to 97.5%. The systemic manifestation is mainly characterized by disruptions on hemostasis with clotting deficiencies, changes on platelet aggregation and fibrinogen depletion, peaking on bleeding events. The mechanism that triggers bleeding is not completely elucidated yet, but at present it is known that, besides metallo proteases, the bothropic venom features serine proteases, particularly thrombin-like enzymes that hydrolyze the fibrinogen only on the ±-chain, and do not activate factor XIII. They form a fibrin net which is more unstable and susceptible to the action of the fibrinolytic system hence contributing to the worsening of the hemorrhage picture. The currently used treatment on accidents by B. jararaca is serum therapy which poli-specific Bothropic anti-venom produced by the Butantan Institute. In spite of being efficient, and causing good neutralization of the metalo proteases present on the venom, the serum does not neutralize some serine proteases which are responsible for clotting disorders. Among these serine proteases there are the simile thrombin enzymes. Therefore, this project aims to design and synthesize peptidic inhibitors for the simile thrombin enzymes, which are not neutralized by the anti-venom currently produced by the Butantan Institute, and are co-responsible for the clotting disorders. The addition of these peptidic inhibitors to the anti-venom will increase its efficacy, hence improving the clinical picture of the envenomed patients and so reducing the number of amputations and deaths. (AU)

Scientific publications

(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)

SILVA, G. M.; BERTO, D. H.; LIMA, C. A.; WAITMAN, K. B.; LIMA, C. F. G.; PREZOTO, B. C.; VIEIRA, M. L.; ROCHA, M. M. T.; GONCALVES, L. R. C.; ANDRADE, S. A.. Synergistic effect of serine protease inhibitors and a bothropic antivenom in reducing local hemorrhage and coagulopathy caused by Bothrops jararaca venom. Toxicon, v. 199, p. 87-93, AUG 2021. (17/00236-5, 13/07467-1, 17/04321-7)

GLORIA MARIA DA SILVA; DANIEL HENRIQUE BERTO DE SOUZA; KAROLINE B. WAITMAN; MATTEO CELANO EBRAM; MELISSA R. FESSEL; IULIU CEZAR ZAINESCU; FERNANDA C. PORTARO; MONTSE HERAS; SONIA A. DE ANDRADE. Design, synthesis, and evaluation of Bothrops venom serine protease peptidic inhibitors. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 27, 2021-01-15. (13/07467-1, 17/04321-7)