Targeting Neuroinflammation and Cognitive Decline: First-in-Class Dual Butyrylcholinesterase and p38α Mitogen-Activated Protein Kinase Inhibitors
The currently approved drugs for the treatment of Alzheimer's disease (AD) fail to address its interconnected pathological processes. Inhibition of butyrylcholinesterase (BChE) and p38α mitogen-activated protein kinase (p38α MAPK) offers an innovative dual approach to mitigate two major drivers of neurodegeneration in AD: cholinergic deficit and neuroinflammation. Using structure-based drug design and a library of known p38α MAPK inhibitors, we developed first-in-class, selective dual BChE/p38α MAPK inhibitors with balanced activity against both targets. The X-ray crystal structures of the two most promising molecules bound to both enzymes were solved. Those ligands effectively reduced the production of proinflammatory markers in vitro and ex vivo in phytohemagglutinin/lipopolysaccharide neuroinflammation models. Remarkably, these compounds also significantly improved cognition in scopolamine- and lipopolysaccharide-induced models of cognitive dysfunction in mice. Because our dual-acting inhibitors target both the symptoms and the underlying neuropathology, they offer an innovative and comprehensive strategy to combat AD.
Authors
- Joanna Gdula‐Argasińska (ORCID: https://orcid.org/0000-0003-3501-8350)
- Ondřej Soukup (ORCID: https://orcid.org/0000-0001-6376-8701)
- Florian Nachon (ORCID: https://orcid.org/0000-0003-0293-2429)
- Xavier Brazzolotto (ORCID: https://orcid.org/0000-0001-9219-1032)
- Stanislav Gobec (ORCID: https://orcid.org/0000-0002-9678-3083)
- Rudolf Andrýs (ORCID: https://orcid.org/0000-0003-1108-3924)
- Alexandre Igert (ORCID: https://orcid.org/0000-0002-0421-6488)
- Damijan Knez (ORCID: https://orcid.org/0000-0001-9917-1384)
- Nataša Tešić
- Elżbieta Wyska (ORCID: https://orcid.org/0000-0002-4798-0574)
- José Dias (ORCID: https://orcid.org/0000-0002-7625-0618)
- Kamil Musílek (ORCID: https://orcid.org/0000-0002-7504-4062)
- Małgorzata Szafarz (ORCID: https://orcid.org/0000-0002-8619-5659)
- Kinga Sałat (ORCID: https://orcid.org/0000-0003-0614-5393)
- Jan Detka (ORCID: https://orcid.org/0000-0002-9866-5777)
- Matic Proj
- Aleš Obreza
- Adam Skarka (ORCID: https://orcid.org/0000-0002-7355-6857)
- Anja Hafner Pišlar (ORCID: https://orcid.org/0000-0002-1159-1024)
- Urban Košak (ORCID: https://orcid.org/0000-0001-7537-0362)
- Urban Švajger (ORCID: https://orcid.org/0000-0002-1908-4254)
- Lenka Pulkrabkova (ORCID: https://orcid.org/0000-0002-8238-4540)
- A. Meden (ORCID: https://orcid.org/0000-0003-3594-6579)
- Natalia Płachtij
- Aleksandra Manik
- Selena Horvat (ORCID: https://orcid.org/0009-0007-2419-6174)
- Svit Ferjančič Benetik
- Katja Krajšek
Institutions
- Jagiellonian University (PL)
- University of Ljubljana (SI)
- Blood Transfusion Centre of Slovenia (SI)
- Therapeutic Health Services (US)
- Institut de Recherche de Chimie Paris (FR)
- University Hospital Hradec Králové (CZ)
- Centre of Biomedical Research (IN)
- University of Hradec Králové (CZ)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-08-08
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00933
- Citations
- 2
- Primary Topic
- Cholinesterase and Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 2.79
Funders
- Northwestern University
- Uniwersytet Jagielloński Collegium Medicum
- Grantová Agentura České Republiky
- Narodowe Centrum Nauki
- Javna Agencija za Raziskovalno Dejavnost RS
- Univerza v Ljubljani
- Ministère des Armées
- National Institutes of Health