Dra. Rosana N. Chehín (Dir.), F. González-Lizárraga1, C. Ávila1, D. Ploper1, S. Socías1, P. P. Michel3, R. Raisman-Vozari3, L. Pietrasanta2, R. Chehín1
1Instituto Medicina Molecular y Celular Aplicada (IMMCA) (CONICETUNT-SIPROSA) Tucumán, Argentina. 2 Departamento de Física – IFIBA (CONIETUBA), and Centro de Microscopías Avanzadas, FCEN- UBA, Buenos Aires – Argentina. 3 Institut du Cerveau et de la Moelle épinière (ICM), Inserm U 1127, CNRS UMR 7225, Sorbonne Université, Paris, France.

Objectives: Parkinson’s disease (PD) is a progressive neurodegenerative condition with age being the main risk factor for its development. This disease has a multifactorial basis and a multi-target treatment is required. The escalating cost of developing new compounds has reinvigorated interest in drug repositioning to accelerate bench to bedside transition. With this in mind, we previously demonstrated that the tetracycline doxycycline (DOX) reshapes oligomeric species of the Parkinson disease protein alpha-synuclein (aS) reducing their toxicity, seeding capacity and propensity to form toxic fibrillar species. However, the antibiotic activity of DOX represents a possible hurdle for its repositioning in long-term treatments. Thus, we sought out to find a non-antibiotic DOX analogue with potent anti-amyloidogenic properties, making this drug an ideal candidate for repurposing to treat PD and conceivably other amyloid-associated disorders.
Methods: In order to detect putative anti-amyloidogenic ready to use molecules, we used chemioinformatic techniques to extract a novel structural motif (Cb-IM) capable of interacting with cross-b structures, and screened a number of pre-existing compounds using this strategy. Incyclinide was selected among tetracyclines because: i) it contains this motif in a planar structure, ii) passes the BBB, and iii) is ready for repurposing. Using a combination of biophysical techniques (fluorescence and infrared spectroscopy, scattering second order, electron microscopy, atomic force microscopy) together with cell biology approaches, we characterized its impact against aS toxic aggregates.
Results: Incyclinide had an exceptional ability to reshape aS oligomers towards less toxic and non-seeding species. Moreover, Incyclinide was able to disrupt mature fibrils and was more efficient than DOX at inhibiting neuroinflammatory processes.
Conclusion: The anti-amyloidogenic and anti-neuroinflammatory properties of Incyclinide, together with its ability to cross the BBB, position Incyclinide as an ideal drug to be repurposed in PD and possibly in other amyloid-associated diseases.