The world still awaits a breakthrough in treating Alzheimer’s disease. How long until we run out of patience? Well, continue reading and you may see a glimmer of hope.

Researchers from the Department of Chemistry and Chemical Engineering at the Syed Babar Ali School of Science and Engineering, under the supervision of Dr. Rahman Shah Zaib Saleem (Associate Professor) have been keeping busy exploring compounds that may help with how we think about treating Alzheimer’s disease. The clockwork that it is, our body responds to certain chemicals in a very specific and predictable way. The rut of the mill method in pharmacological interventions has been to design and deploy compounds in the body that stabilize and sequester Aβ (amyloid-beta peptide). The pathogenesis of Alzheimer’s disease is believed to be driven by the production and deposition of amyloid-beta peptide, or Aβ, in the form of long, slender fibers, as the result of a process known as fibrillization. If an intervention can maneuver around this problem, then the pathway to treating Alzheimer can at least be scouted. In short – this compound is a target of interest!

The team of Dr. Ghayoor Abbas, Dr. Rahman Shah Zaib Saleem and his MS students Umme Kalsoom and Syed Usama, has synthesized a library of selenadiazole-based compounds, that can prevent the fibrillization of Aβ in the neurological tissues, thereby shattering these long, slender molecular spires and preventing fibrillization. This synthesis saw collaboration with Dr. Ghayoor Abbas, who has worked extensively on the applications of iridium-catalyzed aromatic C-H borylation in organic synthesis in the past. The selenadiazole compounds arrest the Aβ molecule in its monomeric form and prevent the ‘graduation’ into oligomerization. This effect was confirmed using a suite of instruments such as ThT assay, CD spectrophotometry, and TEM imaging. 

In this research, other compounds were also studied that affected Aβ fibrillization in different ways, by docking differently to Aβ. For example, some completely inhibit the ‘molecular spires or fibrils from forming, leading to Aβ toxicity that can creep into the blood-brain barrier as well, while others only partially inhibit the process. It turns out that compounds that stabilize the Aβ monomers seem to work best, compared to partial and noninhibitors. The results encourage preclinical development of these ‘magical’ selenadiazole compounds for a potential therapy of Alzheimer’s disease. We wish the best of luck to Dr. Rahman Shah Zaib and his group for the future prospects of this research work.

Reference:

Kalsoom, U., Alazmi, M., Farrukh, H., Chung, K., Alshammari, N., Kakinen, A., Chotana, G., Javed, I., Davis, T. & Saleem, R. Structure Dependent Differential Modulation of Aβ Fibrillization by Selenadiazole-Based Inhibitors. ACS Chemical Neuroscience. https://doi.org/10.1021/acschemneuro.1c00478