How Lego Chemistry can help fight neurodegenerative diseases

The study now published is the result of more than 10 years of research work

Researchers from the Faculty of Sciences of the University of Porto (FCUP) “built” an antioxidant that could result in a drug candidate for neurodegenerative diseases. The secret is in the “chemistry of Lego pieces” and it is not by chance that they gave it this name.

“To combat the changes caused by oxidative stress at the mitochondrial level, an antioxidant must have, in its construction, a perfect set of “pieces” to be able to cross the cell and mitochondrial membrane and thus reach this essential component of our cells. to life”, explains Fernanda Borges, professor at FCUP and researcher at the Center for Research in Chemistry at the University of Porto (CIQUP) who leads the research team. “And we found the perfect fit”, she concludes.

And how did they do it? Piece by piece, just like building a Lego game. “We got an ideal piece that allows, after chemical modulation, to obtain innovative antioxidants directed to the mitochondria, with low toxicity and with a neuroprotective effect”, he describes.

These are the main results of a study published in the most prominent journal in the area of ​​Medicinal Chemistry – Journal of Medicinal Chemistry, with a second article already in the submission phase.

The antioxidant transporters

At the beginning of this construction, which resembles Lego, is the structure of a natural antioxidant, caffeic acid, present in coffee, fruit and vegetables. “The problem is that this type of antioxidant cannot reach the mitochondria, and they also do not have physicochemical properties that guarantee adequate bioavailability: they are very water soluble and therefore easily excreted”, explains the researcher.

“The initial strategy was not to change the structure of the natural antioxidant present in the diet, but to try to insert a vector that would take it to the target site of action”, says the professor.

With the help of chemistry, they added a kind of cationic transporter to this type of antioxidant, to take them to the desired location. The most used to guarantee the entrance of a compound, of natural or synthetic origin in the mitochondria, is the triphenylphosphonium cation (TPP+).

However, “we suspect that this cation may not only interact with the mitochondrial membranes causing damage, but also lead to an excessive accumulation of antioxidants within the organelle, becoming toxic to the cells”, says Carlos Fernandes, researcher at CIQUP and one of the authors of the study.

test the toxicity

Starting from this impasse, the team “played” in a challenge of removing and placing parts with the purpose of replacing this cation. “We had to guarantee that the parts introduced were not toxic”, says Fernanda Borges.

“To do this, we used two cell lines in this study: one neuronal and one hepatic – because we would also have to assess whether the antioxidants caused damage to the liver, which is our main sensor of toxicity.”

After several fitting attempts, the piece with the best results was the cation derived from isoquinoline. “We were able to obtain an antioxidant that enters the mitochondria, but does not cause toxic damage”, conclude the researchers. Furthermore, this antioxidant has shown a neuroprotective effect on cells.

The next steps will be, based on a bilateral agreement with the University of Montpellier, in France, under the Pessoa Program of the Foundation for Science and Technology, to carry out tests in in vivo models with mice. The aim is to test the performance of the best mitochondriotropic antioxidants obtained by the group, thus validating the in vitro results achieved to date.

The study now published is the result of more than 10 years of research work focusing on the study and development of new antioxidants. In addition to Fernanda Borges and Carlos Fernandes, FCUP researchers Sofia Benfeito, Fernando Cagide, Daniel Chavarria, Lisa Sequeira and Sandra Barreiro also signed this article.

FCUP scientists also had the collaboration of professors and researchers from the Faculty of Pharmacy of the University of Porto, the University of Santiago de Compostela and the Center for Neurosciences and Cell Biology of the University of Coimbra.