Neuroprotective Effects of a Novel Demeclocycline Derivative Lacking Antibiotic Activity: From a Hit to a Promising Lead Compound.

Autor: Tomas-Grau R; Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), Pasaje Dorrego 1080, San Miguel de Tucumán 4000, Argentina., González-Lizárraga F; Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), Pasaje Dorrego 1080, San Miguel de Tucumán 4000, Argentina., Ploper D; Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), Pasaje Dorrego 1080, San Miguel de Tucumán 4000, Argentina., Avila CL; Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), Pasaje Dorrego 1080, San Miguel de Tucumán 4000, Argentina., Socías SB; Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), Pasaje Dorrego 1080, San Miguel de Tucumán 4000, Argentina., Besnault P; Paris Brain Institute-ICM, Inserm, CNRS, Sorbonne Université APHP, Hôpital de la Pitié la Pitié-Salpêtrière, 75013 Paris, France., Tourville A; Paris Brain Institute-ICM, Inserm, CNRS, Sorbonne Université APHP, Hôpital de la Pitié la Pitié-Salpêtrière, 75013 Paris, France., Mella RM; Innoprot SL, Parque Tecnológico de Bizkaia, Edificio 502, 48160 Derio, Spain., Villacé P; Innoprot SL, Parque Tecnológico de Bizkaia, Edificio 502, 48160 Derio, Spain., Salado C; Innoprot SL, Parque Tecnológico de Bizkaia, Edificio 502, 48160 Derio, Spain., Rose C; BioCIS, Université Paris-Saclay, CNRS, 92290 Châtenay-Malabry, France., Seon-Méniel B; BioCIS, Université Paris-Saclay, CNRS, 92290 Châtenay-Malabry, France., Brunel JM; UMR_MD1 'Membranes et Cibles Thérapeutiques', U1261 INSERM, Aix-Marseille Université, 13385 Marseille, France., Ferrié L; BioCIS, Université Paris-Saclay, CNRS, 92290 Châtenay-Malabry, France., Raisman-Vozari R; Paris Brain Institute-ICM, Inserm, CNRS, Sorbonne Université APHP, Hôpital de la Pitié la Pitié-Salpêtrière, 75013 Paris, France., Michel PP; Paris Brain Institute-ICM, Inserm, CNRS, Sorbonne Université APHP, Hôpital de la Pitié la Pitié-Salpêtrière, 75013 Paris, France., Figadère B; BioCIS, Université Paris-Saclay, CNRS, 92290 Châtenay-Malabry, France., Chehín R; Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), Pasaje Dorrego 1080, San Miguel de Tucumán 4000, Argentina.
Jazyk: angličtina
Zdroj: Cells [Cells] 2022 Sep 04; Vol. 11 (17). Date of Electronic Publication: 2022 Sep 04.
DOI: 10.3390/cells11172759
Abstrakt: The antibiotic tetracycline demeclocycline (DMC) was recently reported to rescue α-synuclein (α-Syn) fibril-induced pathology. However, the antimicrobial activity of DMC precludes its potential use in long-term neuroprotective treatments. Here, we synthesized a doubly reduced DMC (DDMC) derivative with residual antibiotic activity and improved neuroprotective effects. The molecule was obtained by removal the dimethylamino substituent at position 4 and the reduction of the hydroxyl group at position 12a on ring A of DMC. The modifications strongly diminished its antibiotic activity against Gram-positive and Gram-negative bacteria. Moreover, this compound preserved the low toxicity of DMC in dopaminergic cell lines while improving its ability to interfere with α-Syn amyloid-like aggregation, showing the highest effectiveness of all tetracyclines tested. Likewise, DDMC demonstrated the ability to reduce seeding induced by the exogenous addition of α-Syn preformed fibrils (α-Syn PFF ) in biophysical assays and in a SH-SY5Y-α-Syn-tRFP cell model. In addition, DDMC rendered α-Syn PFF less inflammogenic. Our results suggest that DDMC may be a promising drug candidate for hit-to-lead development and preclinical studies in Parkinson's disease and other synucleinopathies.
Databáze: MEDLINE
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