Incyclinide, a non-antibiotic tetracycline, prevents alpha-synuclein aggregation and disrupts fibrillary forms of the protein

GONZALES LIZARRAGA, MF; AVILA C.; PLOPER D.; SOCIAS, S.B.; PEREIRA M.; MICHEL, P.; RAISMAN VOZARI R.; PIETRASANTA L.; CHEHÍN R.

San Luis

Congreso; XLVIII Reunion Anual de la Sociedad Argentina de Biofísica; 2019

Sociedad Argentina de Biofísica

Parkinson?s disease (PD) is a progressive neurodegenerative illness with age being themain risk factor for its development. The increase in longevity in most Western countriesimposes the urgency of finding a disease-modifying approach for its treatment. Severalpromising molecules targeting PD pathogenic pathways have been proposed but withlimited success. Targeted pathways include notably those regulating α-synucleinaggregation, oxidative stress and neuroinflammation. Due to the multifactorialcharacteristics of the disease, a multitarget drug with efficient activity against theseprocesses is required. With this in mind, we previously demonstrated that thetetracycline doxycycline (DOX) reshapes oligomeric species of the PD protein α-synucleinreducing their toxicity, seeding capacity and propensity to form toxic fibrillary species. Inaddition, DOX showed anti-inflammatory and neuroprotective effects in PD models.However, the antibiotic activity of DOX represents a possible hurdle for its repositioningin long-term treatments. Thus, we sought to find a non-antibiotic DOX analog with potentanti-amyloidogenic properties, making this drug an ideal candidate for repurposing totreat PD and conceivably other amyloid-associated disorders. In order to detect putativeanti-amyloidogenic ready to use molecules, we used cheminformatic methods to extracta novel structural motif capable of interacting with cross-β structures (Cbeta-IM) andscreened a number of pre-existing compounds using this strategy. Incyclinide wasselected among tetracyclines because i) it contains this motif in a planar structure, ii)crosses the BBB, and iii) is available for repurposing. Using a combination of biophysicaltechniques (fluorescence and infrared spectroscopy, second order scattering, differentmicroscopes) together with cell biology approaches, we characterized its impact againstα-synuclein toxic aggregates. Incyclinide had an exceptional ability to reshape α-synuclein oligomers. Moreover, Incyclinide was able to disrupt mature fibrils and thedisassembled species did not trigger a neuroinflammatory response by microglial cells.The anti-amyloidogenic and anti-inflammatory properties of Incyclinide, together with itsability to cross the BBB, position Incyclinide as an ideal drug to be repurposed in PD. Wealso propose the Cbeta-IM as a molecular signature to be exploited for identifying noveldrugs of interest for neuroprotection in PD.