Nell’ottica di sviluppare il peptide PI3Kγ come un nuovo farmaco per uso clinico i ricercatori ne hanno completato l’ottimizzazione chimica, al fine di ottenere una molecola con le caratteristiche di quella originale ma con minor costo per la sintesi. Perciò hanno identificato la sequenza più corta e biologicamente attiva di PI3Kγ. Poi hanno approfondito il meccanismo d’azione della molecola originale nei confronti di CFTR-F508del. A questo scopo hanno condotto esperimenti per misurare le correnti elettriche indotte dalla secrezione epiteliale di cloro (CFTR dipendente) e la quantità di canale espresso in membrana su cellule epiteliali bronchiali F508del. I risultati indicano che il peptide PI3Kγ agisce sia da potenziatore che da correttore del CFTR, e potrebbe essere sfruttato come unico agente terapeutico per il trattamento farmacologico della mutazione CFTR-F508del. Gli studi ulteriori riguarderanno un inquadramento preclinico della sicurezza di PI3Kγ.
In the view of developing PI3Kγ peptide as a novel, human medicinal product researchers completed the chemical optimization of the peptide lead so that to obtain a molecule that recapitulates the biological features of the parent peptide but implying lower cost of synthesis. They identified the minimal active sequence (MIN seq) of PI3Kγ peptide fitted with these properties. Further, they investigated the molecular mechanisms underlying the ability of the parent PI3Kγ peptide to rescue F508del-CFTR function. Chloride current measurements and surface biotinylation assays were carried out in bronchial primary CF and CFBE41o- cells and the resulting data suggest that the PI3Kγ peptide exerts both corrective and potentiating effects and may be exploited as a single agent for the treatment of F508del defect. The PI3Kγ-derived peptide received the Orphan Drug Designation by the European Medicinal Agency (EU/3/17/1859) in 2017 and further studies will be carried out in regard to its preclinical safety assessment.
– Ghigo A, Murabito A, Ren K et al. “Development of a PI3Kγ-derived peptide as a standalone therapy to activate F508del-CFTR, limit lung inflammation and promote bronchorelaxation in Cystic Fibrosis” 15th ECFS Basic Science Conference – Loutraki (Greece) – March 21-24, 2018
– Murabito A, Ren K, Pirozzi F et al. “Exploiting a PI3Kγ Mimetic Peptide as a standalone drug to restore CFTR function, reduce inflammation and limit obstruction of the respiratory tract in cystic fibrosis” SIBBM 2018, Frontiers in Molecular Biology, Rome, Italy, June 20-22, 2018
– Murabito A, Ren K, Pirozzi F et al. “Exploiting a PI3Kγ Mimetic Peptide as a standalone drug to restore CFTR function, reduce inflammation and limit obstruction of the respiratory tract in cystic fibrosis” 15th ECFS Basic Science Conference – Loutraki (Greece) – March 21-24, 2018
– Murabito A, Ren K, Melotti P et al. “Exploiting a PI3KI mimetic peptide as a single molecule with three independent therapeutic benefits in cystic fibrosis” North American Cystic Fibrosis Conference (NACF), October 18-20, 2018, Denver, CO, USA
