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

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 w...

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Autores principales: Tomas-Grau, Rodrigo, González-Lizárraga, Florencia, Ploper, Diego, Avila, César L., Socías, Sergio B., Besnault, Pierre, Tourville, Aurore, Mella, Rosa M., Villacé, Patricia, Salado, Clarisa, Rose, Clémence, Seon-Méniel, Blandine, Brunel, Jean-Michel, Ferrié, Laurent, Raisman-Vozari, Rita, Michel, Patrick P., Figadère, Bruno, Chehín, Rosana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454755/
https://www.ncbi.nlm.nih.gov/pubmed/36078167
http://dx.doi.org/10.3390/cells11172759
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author Tomas-Grau, Rodrigo
González-Lizárraga, Florencia
Ploper, Diego
Avila, César L.
Socías, Sergio B.
Besnault, Pierre
Tourville, Aurore
Mella, Rosa M.
Villacé, Patricia
Salado, Clarisa
Rose, Clémence
Seon-Méniel, Blandine
Brunel, Jean-Michel
Ferrié, Laurent
Raisman-Vozari, Rita
Michel, Patrick P.
Figadère, Bruno
Chehín, Rosana
author_facet Tomas-Grau, Rodrigo
González-Lizárraga, Florencia
Ploper, Diego
Avila, César L.
Socías, Sergio B.
Besnault, Pierre
Tourville, Aurore
Mella, Rosa M.
Villacé, Patricia
Salado, Clarisa
Rose, Clémence
Seon-Méniel, Blandine
Brunel, Jean-Michel
Ferrié, Laurent
Raisman-Vozari, Rita
Michel, Patrick P.
Figadère, Bruno
Chehín, Rosana
author_sort Tomas-Grau, Rodrigo
collection PubMed
description 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.
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spelling pubmed-94547552022-09-09 Neuroprotective Effects of a Novel Demeclocycline Derivative Lacking Antibiotic Activity: From a Hit to a Promising Lead Compound Tomas-Grau, Rodrigo González-Lizárraga, Florencia Ploper, Diego Avila, César L. Socías, Sergio B. Besnault, Pierre Tourville, Aurore Mella, Rosa M. Villacé, Patricia Salado, Clarisa Rose, Clémence Seon-Méniel, Blandine Brunel, Jean-Michel Ferrié, Laurent Raisman-Vozari, Rita Michel, Patrick P. Figadère, Bruno Chehín, Rosana Cells Article 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. MDPI 2022-09-04 /pmc/articles/PMC9454755/ /pubmed/36078167 http://dx.doi.org/10.3390/cells11172759 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tomas-Grau, Rodrigo
González-Lizárraga, Florencia
Ploper, Diego
Avila, César L.
Socías, Sergio B.
Besnault, Pierre
Tourville, Aurore
Mella, Rosa M.
Villacé, Patricia
Salado, Clarisa
Rose, Clémence
Seon-Méniel, Blandine
Brunel, Jean-Michel
Ferrié, Laurent
Raisman-Vozari, Rita
Michel, Patrick P.
Figadère, Bruno
Chehín, Rosana
Neuroprotective Effects of a Novel Demeclocycline Derivative Lacking Antibiotic Activity: From a Hit to a Promising Lead Compound
title Neuroprotective Effects of a Novel Demeclocycline Derivative Lacking Antibiotic Activity: From a Hit to a Promising Lead Compound
title_full Neuroprotective Effects of a Novel Demeclocycline Derivative Lacking Antibiotic Activity: From a Hit to a Promising Lead Compound
title_fullStr Neuroprotective Effects of a Novel Demeclocycline Derivative Lacking Antibiotic Activity: From a Hit to a Promising Lead Compound
title_full_unstemmed Neuroprotective Effects of a Novel Demeclocycline Derivative Lacking Antibiotic Activity: From a Hit to a Promising Lead Compound
title_short Neuroprotective Effects of a Novel Demeclocycline Derivative Lacking Antibiotic Activity: From a Hit to a Promising Lead Compound
title_sort neuroprotective effects of a novel demeclocycline derivative lacking antibiotic activity: from a hit to a promising lead compound
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454755/
https://www.ncbi.nlm.nih.gov/pubmed/36078167
http://dx.doi.org/10.3390/cells11172759
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