Characterization of synthetic and natural inhibitors of the human secreted phospholipase A2 of the group IIA

• Grant number: 09/13902-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: January 01, 2010
• End date: September 30, 2010
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Richard John Ward
• Grantee: Elisângela Aparecida Aragão
• Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 05/54855-0 - Animal toxins: structure, function and biotechnological applications, AP.TEM

Abstract

Phospholipases A2 (PLA2s, EC 3.1.1.4) specifically catalyze the hydrolysis of the sn-2 acid-ester bonds of glycerophospholipids liberating, as product of the catalysis, fatty acid and lysophospholipids. They are found in plants, mammals and in venom of vertebrate and invertebrate animals and are involved in a wide variety of physiological processes. Human secreted phospholipase A2 of the group IIA (hsPLA2 gIIA) is a protein of acute phase of the immune response and its expression is induced during the inflammatory response by endotoxins and cytokines via both autocrine and paracrine processes of clinical relevance. The hsPLA2 gIIA shows bactericidal effect against infection by Staphylococcus aureus, and has marked preference for anionic phospholipids such as phosphatidylglycerol (PG) found in bacterial membranes. A wide variety of PLA2 inhibitors that act against the inflammatory effects of these enzymes have been reported in the literature, including substances derived from plant extracts that act against the inflammatory effects of these enzymes. The therapeutical potential of the medicinal plants traditionally is attributed the class of active constituents, including flavonoids, alkalis, triterpenes and others. Based on the variety of beneficial activities presented by natural compounds such as fucoidan, wedelolactona, quercetin, rutin and betulin, which acting as selective inhibitors of PLA2s, we pretend to evaluate the characterization of these compounds as possible inhibitors of the presented activities for hsPLA2 gIIA. The isolated PLA2 of the venom of Crotalus d. terrificus will be used for a comparative analysis in the inhibition assays of these different compounds. Moreover, the technique of molecular modeling will be used to evaluate the specific regions of interaction between the protein and the compounds, which favors the possibility of development of new drugs against the inflammatory activities of this enzyme. (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)

ARAGAO, ELISANGELA APARECIDA; VIEIRA, DAVI SERRADELLA; CHIOATO, LUCIMARA; FERREIRA, TATIANA LOPES; LOURENZONI, MARCOS ROBERTO; SILVA, SAMUEL REGHIM; WARD, RICHARD JOHN. Characterization of suramin binding sites on the human group IIA secreted phospholipase A(2) by site-directed mutagenesis and molecular dynamics simulation. Archives of Biochemistry and Biophysics, v. 519, n. 1, p. 17-22, MAR 1 2012. (09/13902-7)