Ligand molecular recognition by human transthyretin (TTR): structural bases for binding to TTR and formation inhibition of amyloid fibers in TTR complexes: ligands

• Grant number: 06/01708-3
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): September 01, 2006
• Effective date (End): August 31, 2010
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Igor Polikarpov
• Grantee: Daniela Barretto Barbosa Trivella
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil

Abstract

Tranthyretin amyloid fibril deposition is associated with chronic-degenerative diseases, such as SSA (senile systemic amyloidosis), FAP (familial amyloid polyneuropathy) and FAC (amilial amyloid cardimyopathy). Recently, the effect of low molecular weight chemical compounds on the binding and stabilization capacity of TTR tetramer and consequent amyloid fibril formation inhibition was evaluated, yielding potential lead compounds for drug development against these pathologies. The present research proposal aims to solve the molecular structures of TTR: ligands complexes, as well to determine ligand affinity for TTR and to test the potentiality of amyloidogenesis inhibition by the ligands. We have selected a set of thyroid hormone receptor (TR) ligands (agonists and antagonists): GC-1, GC-24, NH-3 and DITPA; estrogen receptor (ER) ligands: estradiol (agonist), raloxiphen and tamoxiphen (selective modulators), the phytoestrogen genistein and low molecular weight compounds extracted from red wine with potential for ER/TR activation and affinity for TTR. These compounds have a potential as molecules for amyloidogenesis inhibition, and might represent putative pharmacophoric scaffolds for pharmaceutical development.

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)

TRIVELLA, DANIELA B. B.; DOS REIS, CAIO V.; LIMA, LUIS MAURICIO T. R.; FOGUEL, DEBORA; POLIKARPOV, IGOR. Flavonoid interactions with human transthyretin: Combined structural and thermodynamic analysis. Journal of Structural Biology, v. 180, n. 1, p. 143-153, OCT 2012. (09/54035-4, 06/01708-3)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

TRIVELLA, Daniela Barretto Barbosa. Structural and molecular basis of ligand recognition by the human protein transthyretin. 2010. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Física de São Carlos (IFSC/BT) São Carlos.