Miquéias Pacheco – Principal Investigator at the Cystic Fibrosis Research Group (included in the Functional Genomics and Proteostasis Goup), BioISI – Ciências ULisboa – and his team reported the discovery of new compounds that can correct the defects in the most prevalent mutant protein associated to cystic fibrosis, on a recent paper published in the European Journal of Pharmacology. Read this BioISI Digest to know more.
What was the starting point that led to the current research?
One of our interests is to identify novel small molecules that rescue F508del-CFTR, the most prevalent mutant protein in Cystic Fibrosis (CF), a life-threatening genetic disease that affects over 100,000 people worldwide. We thus established an international collaboration with Prof. Camilla Buarque from PUC-Rio (Brazil) in order to use our complementary expertise to achieve this common goal. She designed and synthesised a series of novel compounds, while our research group assessed the biological activity of these compounds by employing biochemical, microscopy and functional assays to identify which compounds corrected mutant CFTR protein folding and trafficking to the cell surface, which are impaired by this mutation.
What is the main finding reported in this paper?
Our results showed that four novel compounds rescue F508del-CFTR mutant protein traffic to the cell surface. These compounds have a triazole scaffold, which is a chemical structure unlike any previously identified CFTR corrector drug.
If you had to explain the main finding to a 5-year-old child, how would you do it?
We can think of mutant CFTR protein as a piece of paper that we want to turn into a cool origami for example, a fox. If we have all the instructions, we can fold the paper correctly until the final origami fox form. However, if some information is missing, we are unable to make it right. Our fox could lack a nail, a pow, or even the head depending on how important is the missing information. In case of a very severe mutation, all we get is crumpled paper. Our work here was to identify which one among several tools (compounds) that could help us to fold properly this paper (i.e., get the mutant protein in a folded, functional form). We tested several tools and then observed that by using a special glue at the beginning of the folding, we could obtain most of the fox origami right in the end, i.e., without losing any important parts.
Why is it important for the scientific community and for society at large?
Despite that four CFTR modulator drugs are currently approved for clinical use, they are very expensive and only partially correct F508del-CFTR defects. It is also estimated that less than 20% of individuals with CF who are eligible to take these drugs are actually getting them, due to their high cost. Therefore, there is still a need to identify novel drugs for CF with greater potency and efficacy not only to achieve greater therapeutic outcomes but also to reduce the financial burden with alternative therapeutic options.
What are the next steps?
Drug development is a long process that requires subsequent advancements in medicinal chemistry to obtain compounds with greater efficacy, potency and selectivity for clinical use. Based on the data obtained on this study, we are now performing additional rounds of medicinal chemistry to optimize and refine these molecules in order to obtain novel compounds with improved pharmacological properties. Ultimately, a company has to be the driver of clinical trials and for that we aim to sell the patent that we already filed with our colleagues from Rio de Janeiro.
Discover more about FunGP Group here.
Read the full paper here.
From left to to right: Mafalda Bacalhau, Miquéias Lopes-Pacheco, Filipa Ferreira, Arthur Kmit and Margarida Amaral [photos provided by the researchers].