A new structural homology model of intact human F508del-CFTR embedded in a phospholipid bilayer and a SPR biosensor containing the same protein in a cell membrane-mimicking lipid film was prepared. These tools, along with appropriate cell-based assays, have been firstly used to analyze a mixed library of well-known and new compounds that allowed the validation of the system and the identification of a promising molecule endowed with an F508del-binding and rescuing capacity that is higher than those of drugs already in use. With the computational model, it was then performed a virtual drug repositioning on a library of 846 drugs, identifying 10 drugs that were reduced to 4 on the basis of toxicity profile and patient compliance. In the extension of this study (Project FFC#10/2019), the already identified drugs will be subjected to experimental characterization aimed at evaluating their effective capacity to bind F508del-CFTR and rescue its activity.

Congress abstracts

• Khabibulina L, Fossa P., La strategia di riposizionamento di farmaci: un utile approccio per identificare nuovi composti per la terapia di fibrosi cistica, Tesi di Laurea in Chimica e Tecnologia Farmaceutica, Università degli Studi di Genova, Scuola di Scienze Mediche e Farmaceutiche (A.A. 2018-19)
• Uggeri M, Orro A, Urbinati C et al. Multidisciplinary approaches to rescue CFTR impairments by drug repositioning, BITS 2019, Bioinformatics Italian Society, Annual Meeting 2019, June 26-28, Palermo
• Uggeri M, Orro A, Urbinati C et al. Rescuing defective CFTR applying a drug repositioning strategy, XXVI National Meeting in Medicinal Chemistry, XII Young Medicinal Chemists’ Symposium, Milan, Ca’ Granda, July 16-19, 2019