20.500.12556/RUL-175854 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. central nervous system inhibition inhibitors peptides and proteins rodent models centralni živčni sistem inhibicija inhibitorji peptidi in beljakovine modeli glodalcev farmacevtska kemija Alzheimerjeva bolezen true false true Angleški jezik Slovenski jezik Članek v reviji 2025-11-11 09:58:59 2025-11-11 09:59:04 2025-12-15 04:07:39 0000-00-00 00:00:00 2025 0 0 Str. 17378−17411 iss. 16 Vol. 68 2025 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54:616.894 1520-4804 10.1021/acs.jmedchem.5c00933 250778371 targeting-neuroinflammation-and-cognitive-decline-first-in-class-dual-butyrylcholinesterase-and-p38α-mitogen-activated.pdf targeting-neuroinflammation-and-cognitive-decline-first-in-class-dual-butyrylcholinesterase-and-p38α-mitogen-activated.pdf 1 A25F629905E43F00581813868B51E48A 6629c8abb9af458510b48be95e9b7fca42a2f34d8f71c2be955ec076828ba2ce 6f4d4f50-d1b2-11f0-9328-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=223043 https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c00933 1 5881c71f-bedc-11f0-9328-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=221761 Fakulteta za farmacijo 0 0 0