A new paper, published in the International Journal of Molecular Sciences, first-authored by Sónia Zacarias, coordinated by Carlos M. Farinha – respectively, researcher and principal investigator at the Cystic Fibrosis Research group, included in the Functional Genomics and Proteostasis Group, and with the collaboration of Bruno L. Victor, PI of the Structure-Based Molecular Modeling Lab; both at Ciências ULisboa – reveals the mode of action of different drugs correctively acting on the deffective protein that causes the disease – , giving valuable insights to develop new therapies for individuals bearing rare variants . Know more below.

What was the starting point that led to the current research?

Here we focused on rare CFTR-causing variants that impair the trafficking of the CFTR protein to the cell surface and assessed if they respond to the current available modulators and whether that response correlates with the localization of the aminoacids in the structure of the protein.

What is the main finding reported in this paper?

As we studied two groups of variants that lie at two specific locations within CFTR structure, we found that the variants in one of the groups all responded to the modulators whereas the ones in the other group didn’t response. As these results suggested a structural location-dependent pattern for correction, we used molecular modeling to try to explain this difference and found that the mutations that didn’t respond to the drugs induce greater destabilization of CFTR structure than those that responded.

If you had to explain the main finding to a 5-year-old child, how would you do it?

We looked at what attacks a protein and leads to disease. We discovered that the protein is stronger at some places than at others and so if we prevent the attack from that side – with a shield (i.e. a drug), we are most likely to have success in avoiding disease.

Why is it important for the scientific community and for society at large?

Our results are relevant as they further contribute to the understanding of the mechanisms of disease in cystic fibrosis, especially when caused by these very rare variants. They also help in clarifying the mode of action for the modulator drugs, and, by characterizing response of the variants to the modulators, the study has the potential to bring these life-changing drugs to individuals bearing these very rare variants – in a personalized medicine approach.

What are the next steps?

The next steps are to add more mutations to this approach – to help unravel molecular mechanisms of disease, mode of action for drugs and to bring therapies to more individuals suffering with this disease.

Know more about FunGP group here.

Read the full paper here.