Tirbanibulin (KX2-391) analog KX2-361 inhibits botulinum neurotoxin serotype A mediated SNAP-25 cleavage in pre- and post-intoxication models in cells.

Autor: Koc D; Department of Biological Sciences, Middle East Technical University, Ankara, Türkiye., Ibis K; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Türkiye., Besarat P; Department of Biological Sciences, Middle East Technical University, Ankara, Türkiye., Banoglu E; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Türkiye., Kiris E; Department of Biological Sciences, Middle East Technical University, Ankara, Türkiye.
Jazyk: angličtina
Zdroj: Drug development research [Drug Dev Res] 2024 Sep; Vol. 85 (6), pp. e22248.
DOI: 10.1002/ddr.22248
Abstrakt: Botulinum neurotoxins (BoNT) inhibit neuroexocytosis, leading to the potentially lethal disease botulism. BoNT serotype A is responsible for most human botulism cases, and there are no approved therapeutics to treat already intoxicated patients. A growing body of research has demonstrated that BoNT/A can escape into the central nervous system, and therefore, identification of BoNT/A inhibitors that can penetrate BBB and neutralize the toxin within intoxicated neurons would be important. We previously identified an FDA-approved, orally bioavailable compound, KX2-391 (Tirbanibulin) that inhibits BoNT/A in motor neuron assays. Recently, a structural analog of KX2-391, KX2-361, has been shown to exhibit good oral bioavailability and cross BBB with high efficiency in mouse experiments. Therefore, in this work, we evaluated the inhibitory effects of KX2-361 against BoNT/A. Toward this goal, we first evaluated the compound for its effects on cell viability in PC12 cells, via MTT assay, and in mouse embryonic stem cell (mESC)-derived motor neurons, with imaging-based assays. Following, we tested KX2-361 in mESC-derived motor neurons intoxicated with BoNT/A holotoxin, and the compound exhibited activity against the toxin in both pre- and post-intoxication conditions. Excitingly, KX2-361 also inhibited BoNT/A enzymatic component (light chain; LC) in PC12 cells transfected with BoNT/A LC. Furthermore, our molecular docking analyses suggested that KX2-361 can directly bind to BoNT/A LC. Medicinal chemistry approaches to develop structural analogs of KX2-361 to increase its efficacy against BoNT/A may provide a critical lead compound with BBB penetration capacity for drug development efforts against BoNT/A intoxication.
(© 2024 The Author(s). Drug Development Research published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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