CONICET | Buscador de Institutos y Recursos Humanos

Parkinson?s disease (PD) is an aging-related neurodegenerative disordercharacterized by the aggregation of α-synuclein in dopaminergicneurons. Considering projections of the world?s future population, the number ofpeople with PD will reach around 14 million in 2040 and threatens to breakdownhealthcare systems worldwide. Unfortunately, drug development programs need10 to 17 years from bench to bed. Approaches such as drug repurposing andrepositioning save time by using pre-exiting and approved drugs for newindications. In this way, we demonstrated that doxycycline is able to reshapealpha-synuclein oligomeric species reducing their toxicity, seeding capacity andpropensity to form fibrillar species. However, the antibiotic activity of doxycyclinerepresents 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 exceptionalcharacteristics to interact and reshape/disrupt cross-beta structure. By using acombination of biophysical techniques, we demonstrated that this moleculeinhibits alpha-synuclein aggregation and remodels mature fibrils. Moreover, it hasstriking physicochemical properties to cross the brain blood barrier and is moreefficient than doxycycline inhibiting neuroinflammation. This property, togetherwith its antioxidant, antiaggregant, and anti-inflammatory effects, renders CMT-3as an ideal drug to be repurposed and enter clinical trials for PD and othersynucleopathies.134

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