Labaditin and its modified analogs: structural, conformational studies and interactions with membranes

• Grant number: 06/05186-1
• Support Opportunities: Scholarships in Brazil - Master
• Start date: September 01, 2007
• End date: August 31, 2009
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Pietro Ciancaglini
• Grantee: Simone Cristina Barbosa
• Host Institution: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto (FFCLRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Labaditin is a cyclic decapeptide found in the latex of Jatropha multifida, Euphorbiaceae family. Some characteristics shown by this class of biomolecules are a head-tail cyclization and high hydrophobic aminoacid proportion, which favors the affinity with biological membranes. Studies demonstrated that Labaditina has inhibitory power over the activation of the classic path of the human complementary system which explains the use of the plant as anti-inflammatory in popular medicine. Additionally, this biomolecule has revealed expressive inhibitory power of acetylcholinesterase, of great importance in treating Alzheimer's disease and children with mental retard, aiming to increase their cognitive capacity. Based on the biological activity exhibited and on the high hydrophobic character, the labaditin stands as an important prototype in the development of new drugs. Then, the detailed knowledge of its action mechanisms and structural changes in relation to biological membranes and other media is fundamental. With the aid of peptide synthesis techniques in solid phase, the peptide Labaditin and its modified analogs will be synthesized to evaluate the importance of cyclic structure and of the tryptophane residues which have an important role in the peptide-membrane interaction. So, these molecules will be studied by circular dichroism (structural change analysis), fluorescence (elucidation of the mechanisms of action) and calorimetry (determination of the structural dynamic changes in the membrane caused by the peptide, as well as parameters of denaturation and bonding constants of the peptide). These studies will be done and evaluated in various conditions, including interactions with natural membrane systems (erythrocyte) and artificial (liposomes), with the purpose to understand the possible mechanism of action of these peptides. Besides the interaction and structural change studies, we will evaluate the cytotoxic and erythrocyte activities, in order to search for new possibilities of therapeutical applications. (AU)