Molecular interactions between Doxycycline (and derivatives) and cell membrane models

The project consists of investigating, through biophysical techniques, the interaction of doxycycline (DOX) and its derivatives with cell membrane models in the context of Parkinson’s disease (PD). This neurodegenerative disorder, classified as an α-synucleinopathy, is characterized by the abnormal aggregation of the α-synuclein protein, which leads to neuronal dysfunction and the degeneration of dopaminergic neurons. Previous studies have shown that doxycycline, a well-known tetracycline antibiotic, also exhibits neuroprotective effects. It can inhibit α-synuclein aggregation and modulate inflammatory processes in the nervous system by acting on signaling pathways such as p38 MAPK and NF-κB. Based on these findings, eighteen structural derivatives of doxycycline were developed to enhance its neuroprotective activity while minimizing its antimicrobial effects. Some of these derivatives proved more effective than the original doxycycline in inhibiting α-synuclein aggregation and reducing inflammatory responses in microglial cell cultures. Moreover, they preserved beneficial effects related to neuronal plasticity and growth. The project seeks to deepen the understanding of their interactions with biomimetic cell membranes and supramolecular protein assemblies, such as amyloid fibrils and α-synuclein condensates. By clarifying these molecular mechanisms, this study aims to support the development of new, more effective, and safer therapeutic strategies for neurodegenerative diseases such as Parkinson’s disease, highlighting the potential of doxycycline and its derivatives as neuroprotective agents. We have already conducted differential scanning calorimetry (DSC) experiments using different proportions of doxycycline (DOX) and its derivative DDOX with lipid systems composed of DMPC and DMPG. The results revealed clear changes in the thermal profile of the membranes, indicating that the drug does interact with the lipid bilayer, altering its phase transition temperature and thermodynamic parameters. Our data suggest that the drug associates superficially with the membrane, altering its phase behavior. Techniques including fluorescence spectroscopy, optical microscopy, and electron paramagnetic resonance (EPR) will be employed to complement and expand upon the initial DSC findings. Based on these findings, we are now moving forward to investigate the specific region or depth within the membrane where the drug binds.

This work was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), the São Paulo Research Foundation (FAPESP), and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).