Investigation of peptide-peptide interactions site using the photochemical and photophysical properties of the cis-[Ru(dmphen)2(Aepy)2]2+ luminescent complex

• Grant number: 23/17575-8
• Support Opportunities: Scholarships in Brazil - Master
• Start date: April 01, 2024
• End date: March 31, 2026
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Principal Investigator: Rose Maria Carlos
• Grantee: Ana Carla Candido da Silva
• Host Institution: Centro de Ciências Exatas e de Tecnologia (CCET). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
• Associated scholarship(s): 25/07883-2 - Controlling Amyloid-¿ Aggregation through Photoactive Ru(II) Complexes, BE.EP.MS

Abstract

Alzheimer's disease (AD), the most common among dementias, is a devastating neurodegenerative disease and one of the biggest concerns for public health networks in the world. The pathological characteristic of AD are the senile plaques formed mainly by the aggregation of amyloid beta peptide (bA). Despite the importance of bA1-42 aggregates in the molecular etiology of AD, the amino acid sequence that determines aggregation has not been elucidated. Although several studies indicate that the hydrophobic regions of bA are the most prone to aggregation and fibrillogenesis, the mechanism by which this occurs has not yet been defined. On the other hand, several studies also show that electrostatic interactions stabilize the bA structure by hydrogen bonds, strengthening the antiparallel arrangements for aggregation. Therefore, studies involving the analysis of these regions are important in elucidating the fibrillar core of aggregation and the mechanism that leads to toxic species of bA1-42. Based on these proposal in this project we intend to investigate the influence and effect of the photophysical and photochemical properties of the cis-[Ru(mphen)2(Aepy)2]2+ complex, (RuAepy, mphen = 5,6-dimethyl-phenanthroline, Aepy = 4-(2-aminoethyl)pyridine in the kinetic mechanism of bA1-42 aggregation and cytotoxicity towards human neuroblastoma cells derived from the SH-SY5Y cell line. In vivo toxicity will be evaluated with animal models of Alzheimer's disease (control mice and 5xTgAD transgenics). The RuAepy complex was designed to increase hydrophobic interactions and facilitate hydrogen bonds with hydrophobic and polar residues of bA1-42, inhibiting interactions between peptide chains that lead to fibrillation of bA1-42. To complement this evaluation, the studies will be extended to the fragments bA21-40, which is the C-terminal hydrophobic region, and bA1-28, the N-terminal region of bA. We also intend to investigate whether the products obtained by continuous light irradiation of the RuAepy complex (if the complex is photodissociative) can result in covalent interactions with bA1-42, inhibiting aggregation by a photochemical mechanism. The photophysical properties of the RuAepy complex make it possible to monitor the bA aggregation process through changes in the luminescent responses of the complex.These studies may contribute to the elucidation of the influence of the C-terminal hydrophobic region on the molecular mechanism of bA aggregation as well as the development of new anti-amyloid therapies for AD. This project is part of the regular FAPESP project (proc. 2022-06637-0)