Mafalda Bacalhau and Miquéias Pacheco, respectively, researcher and principal investigator from the Cystic Fibrosis Research Group  (included in the Functional Genomics and Proteostasis – FunGP – Goup), BioISI – Ciências ULisboa – and their team reported the discovery of four new compounds that potentiate the function of the protein that is defective in Cystic Fibrosis, in a recent paper published in the Journal of Personalized Medicine. Read this BioISI Digest to know how these molecules can be a potential innovative therapy for people with CF carrying a rare mutation.  

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

We have been using high-throughput screening assays to identify novel small molecules that can rescue mutant CFTR, the protein that is defective in Cystic Fibrosis (CF). In collaboration with Prof. Camilla Buarque from PUC-Rio (Brazil), a novel collection of compounds was designed and synthesized, and we then performed various assays to identify which compounds could potentiate R334W-CFTR function, a mutation that has minimal impact on CFTR folding and trafficking but significantly reduces channel conductance.

What is the main finding reported in this paper?

The main finding of this study was that four novel compounds potentiated R334W-CFTR function with an additive effect in combination with VX-770, another potentiator that is approved for clinical use. Furthermore, these novel compounds have different scaffolds from that of previous potentiators.

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

We can imagine the mutant CFTR protein as a closed door that we want to open. Our work here was to identify which one among many keys (i.e., compounds) could properly fit in the lock to open the door. After testing several keys, we observed that four keys, which had a similar format, were able to unlock the door.

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

Despite that four CFTR modulators are currently approved for clinical use, CFTR mutations are not equally responsive to these drugs. The R334W is a rare CF-causing mutation (~0.3% of CF alleles worldwide) but has a relatively higher prevalence in Portuguese and Brazilian CF populations (2.8% and 2.3% of CF alleles, respectively). Moreover, no CFTR modulator drug is currently approved for this mutation and there is therefore an urgent need to identify effective therapies for people with CF carrying this mutation.

What are the next steps?

This study was a proof-of-concept that certain CF-causing mutations may benefit from an initial development of mutation-specific modulation, which may be subsequently expanded to other mutations. Our next step is to assess the efficacy of these active compounds in other CF mutations with similar defects as R334W-CFTR. Moreover, we are now performing additional rounds of medicinal chemistry based on the data obtained in this study to optimize and refine these molecules in order to obtain novel compounds with improved pharmacological properties.

Find out more about the FunGP group here

Read the full paper here.

From Left to Right: Mafalda Bacalhau, Miquéias Lopes-Pacheco, Filipa Ferreira, Iris Silva and Margarida Amaral [images provided by the researchers]