A STRUCTURAL BIOLOGY APPROACH TO THERAPEUTIC PRION PROTEIN LIGANDS

• Grant number: 16/22929-0
• Support Opportunities: Scholarships abroad - Research
• Start date: March 01, 2017
• End date: February 28, 2018
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Maria Cristina Nonato
• Grantee: Maria Cristina Nonato
• Host Investigator: Stuart L Schreiber
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: Broad Institute, United States

Abstract

Prion diseases are rare neurodegenerative conditions associated with the conformational conversion of the cellular prion protein PrPC into PrPSc, a self-replicating isoform (prion) that accumulates in the central nervous system of affected individuals. The molecular mechanisms underlying the PrPC-to-PrPSc conversion and subsequent aggregation remain to be elucidated. No specific therapeutic and prophylactic interventions are available for prion diseases. The structure of PrPSc is poorly defined, and likely to be heterogeneous, as suggested by the existence of different prion strains. Designing therapeutics that target PrPC may provide an opportunity to overcome these problems. PrPC ligands may theoretically inhibit the replication of multiple prion strains, by acting on a common site of any prion replication reaction. Researchers at Broad Institute have recently identified potential ligands for PrPc. Interested in contributing in the search for active compounds to treat prion diseases, the present project aims to combine our expertise and the state-of-art techniques and instrumentation in the field of structural biology to characterize the mechanism of interaction between the potential ligands and PrPc. By exploring X-ray crystallography together with different biophysical methods, our results will help to validate and characterize the ligand binding mechanism to PrPc, provide the framework for the design of a new generation of ligands and might contribute to the understanding of the structural plasticity of proteins.

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)

BORTOT, LEANDRO OLIVEIRA; RANGEL, VICTOR LOPES; PAVLOVICI, FRANCESCA A.; EL OMARI, KAMEL; WAGNER, ARMIN; BRANDAO-NETO, JOSE; TALON, ROMAIN; VON DELFT, FRANK; REIDENBACH, ANDREW G.; VALLABH, SONIA M.; et al. Novel quaternary structures of the human prion protein globular domain. Biochimie, v. 191, p. 118-125, DEC 2021. (16/22929-0, 17/26559-5)