Neuroprotective Effects of a Novel Demeclocycline Derivative Lacking Antibiotic Activity: From a Hit to a Promising Lead Compound.
Parkinson’s disease
neuroprotection
novel tetracycline
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
04 09 2022
04 09 2022
Historique:
received:
28
07
2022
revised:
29
08
2022
accepted:
30
08
2022
entrez:
9
9
2022
pubmed:
10
9
2022
medline:
14
9
2022
Statut:
epublish
Résumé
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
Identifiants
pubmed: 36078167
pii: cells11172759
doi: 10.3390/cells11172759
pmc: PMC9454755
pii:
doi:
Substances chimiques
Anti-Bacterial Agents
0
Neuroprotective Agents
0
Lead
2P299V784P
Demeclocycline
5R5W9ICI6O
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
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