CONICET | Buscador de Institutos y Recursos Humanos

Parkinson?s disease (PD) is an aging-related neurodegenerative disorder characterized by the aggregation of α-synuclein in dopaminergic neurons. Considering projections of the world?s future population, the number of people with PD will reach around 14 million in 2040 and threatens to breakdown healthcare systems worldwide. Unfortunately, drug development programs need 10 to 17 years from bench to bed. Approaches such as drug repurposing and repositioning save time by using pre-exiting and approved drugs for new indications. In this way, we demonstrated that doxycycline is able to reshape alpha-synuclein oligomeric species reducing their toxicity, seeding capacity and propensity to form fibrillar species. However, the antibiotic activity of doxycycline represents a hurdle for its repositioning in long-term treatments. Then, we searched for molecules that preserve the antiaggregant, anti-neuroinflammatory and antioxidant properties of doxycycline but with reduced or null antibiotic effect to be studied as candidates for repositioning.According to our results, CMT3, a chemically modified tetracycline, has exceptional characteristics to interact and reshape/disrupt cross-beta structure. By using a combination of biophysical techniques, we demonstrated that this molecule inhibits alpha-synuclein aggregation and remodels mature fibrils. Moreover, it has striking physicochemical properties to cross the brain blood barrier and is more efficient than doxycycline inhibiting neuroinflammation. This property, together with its antioxidant, antiaggregant, and anti-inflammatory effects, renders CMT-3 as an ideal drug to be repurposed and enter clinical trials for PD and other synucleopathies.