CMT-3 inhibits alfa-synuclein aggregation and remodels its mature fibrils: a possible ready to use neuroprotector

GONZÁLEZ LIZARRAGA, MARÍA FLORENCIA; SEQUEIRA, SABRINA; ÁVILA, CÉSAR LUIS; PLOPER, DIEGO; SOCÍAS, BENJAMÍN; BARBOSA, LEANDRO; ITRI, ROSANGELA; RAISMAN-VOZARI, RITA; PIETRASANTA, LÍA ; CHEHÍN, ROSANA NIEVES

La Plata

Congreso; XLVII Reunión Anual de la Sociedad Argentina de Biofísica; 2018

Sociedad Argentina de Biofísica

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 ofpeople with PD will reach around 14 million in 2040 and threatens to breakdown healthcare systems worldwide. Unfortunately, drug development programs need10 to 17 years from bench to bed. Approaches such as drug repurposing and repositioning save time by using pre-exiting and approved drugs for newindications. 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, wesearched for molecules that preserve the antiaggregant, anti-neuroinflammatoryand antioxidant properties of doxycycline but with reduced or null antibiotic effectto 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.