In this action, we proposed the development of novel small molecules capable to inhibit IKKB which is a protein crucial for the activation of NF-κB, the key regulator of inflammation in glial cells of ALS patients, and at the same time presenting iron chelation properties to minimize the effect of the toxic accumulation of iron observed in the tissues of ALS patients and trigger the expression of pro-survival and neurotrophic genes in MNs.
In this action, we started by designing a library of multitarget small molecules after applying two virtual screening filters to select the most promising compounds to interact with IKKB and with the most promising profile for BBB permeation we selected a library of 20 potential multitarget small molecules. The small library was then synthesised by newly developed synthetic routes and after evaluating their iron and antioxidant capacity we selected 16 compounds for our in-vitro cellular cytotoxicity and neuroprotective studies. From our cellular screening studies, 13 and 14 were selected as the most promising Lead. Additionally, our preliminary studies of some properties that may influence the 13 and 14 ADMET profiles revealed that the compounds present a % of HSA binding that suggests higher bioavailability than Edaravone, Riluzole and Deferiprone. The BBB permeability profile of 13 and 14 was also better than at least the one predicted for Edaravone and Deferiprone and worse than Riluzole's passive permeability profile through BBB.
Several activities were conducted to ensure the efficient dissemination and exploitation of the results obtained throughout the action. Therefore, to share our results with our peers and receive their feedback the researcher participated in two international conferences where the results of his work were presented. The researcher was also invited to deliver two oral communications in the scientific meetings organized by the chemistry students from the UC and the UP. The researcher also acquired experience in the supervision of one undergraduate student project and participated in the co-supervision of one Master Student (ongoing) project during which some results of this project were acquired and then presented in the form of a final report. Furthermore, the researcher also submitted one review that is currently in a peer review process where he described the potential of developing drugs for ALS for the targets highlighted in this action. The work developed in this action is still ongoing and already revealed that our discoveries may have major scientific impacts therefore, shortly at least 2 more papers describing the results of our work will be submitted for peer review.
The work and experience gathered during this action encouraged the researcher to establish new collaborations and to apply for research funding to support projects related to the topic of this project. Hence, the researcher also explored the results of this work for a grant application for one exploratory project from FCT to captivate funding to further progress the project developed herein and to achieve the scientific goals not achieved during the action. Additionally, he also participated in the preparation of several grant proposals aiming to develop and/or validate novel therapeutic approaches for ALS under the MSCA-ITN, FCT and other granting schemes. Two of these grant applications were successful and the researcher is currently a member of the research teams of two collaborative projects funded by the FCT granting schemes.
