Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 2 August 2022 / Approved: 3 August 2022 / Online: 3 August 2022 (12:08:08 CEST)

A peer-reviewed article of this Preprint also exists.

Tomas-Grau, R.; González-Lizárraga, F.; Ploper, D.; Avila, C.L.; Socías, S.B.; Besnault, P.; Tourville, A.; Mella, R.M.; Villacé, P.; Salado, C.; Rose, C.; Seon-Méniel, B.; Brunel, J.-M.; Ferrié, L.; Raisman-Vozari, R.; Michel, P.P.; Figadère, B.; Chehín, R. Neuroprotective Effects of a Novel Demeclocycline Derivative Lacking Antibiotic Activity: From a Hit to a Promising Lead Compound. Cells 2022, 11, 2759. Tomas-Grau, R.; González-Lizárraga, F.; Ploper, D.; Avila, C.L.; Socías, S.B.; Besnault, P.; Tourville, A.; Mella, R.M.; Villacé, P.; Salado, C.; Rose, C.; Seon-Méniel, B.; Brunel, J.-M.; Ferrié, L.; Raisman-Vozari, R.; Michel, P.P.; Figadère, B.; Chehín, R. Neuroprotective Effects of a Novel Demeclocycline Derivative Lacking Antibiotic Activity: From a Hit to a Promising Lead Compound. Cells 2022, 11, 2759.

Abstract

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 po-tential use in long-term neuroprotective treatments. Here, we synthesized a DMC derivative with residual antibiotic activity and improved neuroprotective effects. The molecule, called de-rivative demeclocycline (DDMC), was obtained by the removal of both dimethylamino substitu-ents 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-SynPFF ) in ex vitro models and in SH-SY5Y-α-Syn-tRFP cells. In addition, in the presence of DDMC, α-SynPFF were less inflammogenic, as they dampened the release of tumor necrosis factor α (TNF-α) and glutamate by microglial cells compared to control fibrils. Our results suggest that DDMC may be a promising drug candidate for hit-to-lead development and preclinical studies in PD and other synucleinopathies.

Keywords

Parkinson’s disease; novel tetracycline; neuroprotection

Subject

Medicine and Pharmacology, Neuroscience and Neurology

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our Diversity statement.

Leave a public comment
Send a private comment to the author(s)
* All users must log in before leaving a comment
Views 0
Downloads 0
Comments 0
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.