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A new work published in Angew. Chem. Int. Ed. and directed by Drs. Ana Martínez and Valle Palomo, from the Margarita Salas Center for Biological Research (CSIC), presents the development of a series of novel compounds with multitarget action against three different biological targets related to key pathological processes in Alzheimer's disease. These compounds have been obtained using the synthetic methodology known as click chemistry.
Multitarget compounds have gained great relevance for the treatment of complex diseases, such as neurodegenerative pathologies. The work by Nozal et al. describes the design, synthesis, biological evaluation, and computational characterization of new multitarget-modulating agents for Alzheimer's disease.
The synthesized molecules interact specifically with more than one pharmacological target simultaneously and present up to three different biological activities related to the main pathological mechanisms of Alzheimer's disease: the production of the β-amyloid peptide that forms senile plaques, and the hyperphosphorylation of tau resulting in the formation of neurofibrillary tangles. These compounds are inhibitors of the BACE-1 protease, which is the macromolecule responsible for the formation of the β-amyloid peptide, as well as two different kinases that hyperphosphorylate the tau protein.
Cellular assays in models of Alzheimer's disease have allowed the authors to confirm both the multiple pharmacological actions and the applicability of these multitarget ligands. Furthermore, computational studies have demonstrated that these compounds fit adequately at the catalytic site of BACE-1.
Additionally, the work shows the power of the in situ click chemistry methodology, which has been shown to be a versatile synthetic tool that allows reducing the number of compounds that are synthesized. BACE-1 has been used as a template for organic synthesis so that the protein preferentially selects those pairs of kinase inhibitor fragments that give rise to a final compound that inhibits the action of the protease.
Taken together, these results show not only the potential of multitarget-modulating agents for the treatment of neurodegenerative diseases such as Alzheimer's but also the ability of the synthetic methodology to boost the selection of fragments that will be developed into other multitarget drugs.
Reference: From Kinase Inhibitors to Multitarget Ligands as Powerful Drug Leads for Alzheimer’s Disease using Protein-Templated Synthesis. Vanesa Nozal, Alfonso García-Rubia, Eva P. Cuevas, Concepción Pérez, Carlota Tosat-Bitrián, Fernando Bartolomé, Eva Carro, David Ramírez, Valle Palomo, and Ana Martínez (2021) Angew. Chem. Int. Ed. https://onlinelibrary.wiley.com/doi/full/10.1002/anie.202106295