Exploiting the therapeutic potential of ready-to-use drugs: Repurposing antibiotics against amyloid aggregation in neurodegenerative diseases

Abstract

Neurodegenerative diseases are chronic and progressive disorders that affect specific regions of the brain, causing gradual disability and suffering that results in a complete inability of patients to perform daily functions. Amyloid aggregation of specific proteins is the most common biological event that is responsible for neuronal death and neurodegeneration in various neurodegenerative diseases. Therapeutic agents capable of interfering with the abnormal aggregation are required, but traditional drug discovery has fallen short. The exploration of new uses for approved drugs provides a useful alternative to fill the gap between the increasing incidence of neurodegenerative diseases and the long-term assessment of classical drug discovery technologies. Drug re-profiling is currently the quickest possible transition from bench to bedside. In this way, experimental evidence shows that some antibiotic compounds exert neuroprotective action through anti-aggregating activity on disease-associated proteins. The finding that many antibiotics can cross the blood-brain barrier and have been used for several decades without serious toxic effects makes them excellent candidates for therapeutic switching towards neurological disorders. The present review is, to our knowledge, the first extensive evaluation and analysis of the anti-amyloidogenic effect of different antibiotics on well-known disease-associated proteins. In addition, we propose a common structural signature derived from the antiaggregant antibiotic molecules that could be relevant to rational drug discovery.

Peptide‐Based Molecular Strategies To Interfere with Protein Misfolding, Aggregation, and Cell Degeneration

“…Finally, an example of inhibitors derived from interaction partners are gramicidin S (GS) derived decapeptides; these were found by Abrahams and co‐workers to inhibit Aβ40 fibrillogenesis . Although GS is hemolytic, its analogues and other cyclic antibiotics could become promising anti‐amyloid drug candidates, as drug reprofiling is a fast way to reach the patient …”

CMT-3 targets different α-synuclein aggregates mitigating their toxic and inflammogenic effects

“…Yet, a 2016 retrospective study in a Danish cohort showed that the use of a tetracycline therapy appeared to reduce the risk of PD 25 . This finding revived interest in therapeutic use of tetracyclines for PD 26 .…”

Mikrobiom und neurodegenerative Erkrankungen

“…Außerdem wurde ein neuroprotektiver Effekt von Minocyclin in einem PD-Mausmodell erzielt [22]. Obwohl auch positive Auswirkungen von Antibiotika auf Patienten mit neurodegenerativen Erkrankungen beschrieben sind, u. a. die Reduktion der Aβ-Plaques [19], ist eine individuelle, auf den Stand der Erkrankung angepasste Antibiotikaempfehlung noch nicht in Sicht. Dies ist jedoch umso wichtiger, da von einer prophylaktischen Behandlung abzuraten ist.…”