During the early stages of the project (Phases 1, Phase 2, and Phase 3), two families of compounds, PP and SH, were identified and shown to exhibit significant corrective activity on mutated CFTR protein function. Some of these compounds demonstrated dual activity, acting both as correctors and potentiators; this finding will require further investigation through additional analyses of the interactions between the compounds and the mutated CFTR protein.
The study will continue with the optimization of compound–CFTR interactions, supported by computational approaches such as molecular docking. At this stage of the project, the pharmacokinetic properties (absorption, distribution, metabolism, and excretion) of a selected panel of compounds will also be evaluated through in vivo studies. In addition to the collaboration with the Foundation’s Primary Cell Culture Service, certain preclinical evaluation assays will be outsourced to a Contract Research Organization (CRO) to ensure high-quality analytical standards.
RESULTS
In the fourth phase of the project, researchers used chemical synthesis and functional analysis techniques to optimize the interaction between the new compounds and the CFTR protein. In particular, researchers focused on optimizing the flexibility and length of the molecules to make them more efficient at binding to the CFTR protein.
The new molecules obtained in this way were tested on human bronchial cells in the laboratory and on bronchial epithelial cells from people with CF (thanks to the Primary Culture Service of FFC Ricerca).
Through chemical synthesis cycles, 550 molecules belonging to the two PP and SH families have been generated so far. In particular, two subfamilies of PP compounds, called AL and FLM, have been identified as particularly promising for the recovery of mutated CFTR.
The best PP and SH compounds have been tested in combination with correctors from the Task Force for Cystic Fibrosis project, demonstrating their ability to express a strong synergistic effect, making them promising compounds for future combinations.
Two compounds, PP028 and SH157A, were tested in vivo on an animal model in collaboration with the Translational Pharmacology facility of the Italian Institute of Technology (IIT) in Genoa. These studies indicated that oral bioavailability (i.e., the amount of drug absorbed into the bloodstream and therefore circulating) is moderate and needs to be improved.
The project will continue into phase 5.
who adopted the project
Delegazione FFC Ricerca di Palermo e Trapani
€ 50.000
Rotary Distretto 2060
€ 28.000
Gruppo di sostegno FFC Ricerca di Matera
€ 12.000