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

GONZÁLEZ-LIZÁRRAGA, FLORENCIA; AVILA, CÉSAR L.; PLOPER, DIEGO; SOCIAS, SERGIO B.; PEREIRA, MAURICIO; MICHEL PATRICK; RAISMAN-VOZARI, RITA; PIETRASANTA, LÍA; CHEHÍN, ROSANA

San Luis

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

Sociedad Argentina de Biofísica

Parkinson?s disease (PD) is a progressive neurodegenerative illness with age being the main risk factor for its development. The increase in longevity in most Western countries imposes the urgency of finding a disease-modifying approach for its treatment. Several promising molecules targeting PD pathogenic pathways have been proposed but with limited success. Targeted pathways include notably those regulating α-synuclein aggregation, oxidative stress and neuroinflammation. Due to the multifactorial characteristics of the disease, a multitarget drug with efficient activity against these processes is required. With this in mind, we previously demonstrated that the tetracycline doxycycline (DOX) reshapes oligomeric species of the PD protein α-synuclein reducing their toxicity, seeding capacity and propensity to form toxic fibrillary species. In addition, DOX showed anti-inflammatory and neuroprotective effects in PD models. However, the antibiotic activity of DOX represents a possible hurdle for its repositioning in long-term treatments. Thus, we sought to find a non-antibiotic DOX analog with potent anti-amyloidogenic properties, making this drug an ideal candidate for repurposing to treat PD and conceivably other amyloid-associated disorders. In order to detect putative anti-amyloidogenic ready to use molecules, we used cheminformatic methods to extract a novel structural motif capable of interacting with cross-β structures (Cbeta-IM) 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) crosses the BBB, and iii) is available for repurposing. Using a combination of biophysical techniques (fluorescence and infrared spectroscopy, second order scattering, different microscopes) together with cell biology approaches, we characterized its impact against α-synuclein toxic aggregates. Incyclinide had an exceptional ability to reshape α- synuclein oligomers. Moreover, Incyclinide was able to disrupt mature fibrils and the disassembled species did not trigger a neuroinflammatory response by microglial cells. The anti-amyloidogenic and anti-inflammatory properties of Incyclinide, together with its ability to cross the BBB, position Incyclinide as an ideal drug to be repurposed in PD. We also propose the Cbeta-IM as a molecular signature to be exploited for identifying novel drugs of interest for neuroprotection in PD.