Cystic fibrosis (CF) is an autosomal recessive disorder characterized by respiratory failure due to a vicious cycle of defective Cystic Fibrosis Transmembrane conductance Regulator (CFTR) function, chronic inflammation and recurrent bacterial and fungal infections. Although the recent introduction of CFTR correctors/potentiators has revolutionized the clinical management of CF patients, resurgence of inflammation and persistence of pathogens still posit a major concern and should be targeted contextually. On the background of a network-based selectivity that allows to target the same enzyme in the host and microbes with different outcomes, we focused on sphingosine-1-phosphate (S1P) lyase (SPL) of the sphingolipid metabolism as a potential candidate to uniquely induce anti-inflammatory and antifungal activities in CF. As a feasibility study, herein we show that interfering with S1P metabolism improved the immune response in a murine model of CF with aspergillosis while preventing germination of Aspergillus fumigatus conidia. In addition, in an early drug discovery process, we purified human and A. fumigatus SPL, characterized their biochemical and structural properties, and performed an in silico screening to identify potential dual species SPL inhibitors. We identified two hits behaving as competitive inhibitors of pathogen and host SPL, thus paving the way for hit-to-lead and translational studies for the development of drug candidates capable of restraining fungal growth and increasing antifungal resistance.

Dual species sphingosine-1-phosphate lyase inhibitors to combine antifungal and anti-inflammatory activities in cystic fibrosis: a feasibility study / Cellini, Barbara; Pampalone, Gioena; Camaioni, Emidio; Pariano, Marilena; Catalano, Flavia; Zelante, Teresa; Dindo, Mirco; Macchioni, Lara; Di Veroli, Alessandra; Galarini, Roberta; Paoletti, Fabiola; Davidescu, Magdalena; Stincardini, Claudia; Vascelli, Gianluca; Bellet, Marina Maria; Saba, Julie; Giovagnoli, Stefano; Giardina, Giorgio; Romani, Luigina; Costantini, Claudio. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 13:1(2023), p. 22692. [10.1038/s41598-023-50121-4]

Dual species sphingosine-1-phosphate lyase inhibitors to combine antifungal and anti-inflammatory activities in cystic fibrosis: a feasibility study

Catalano, Flavia;Giardina, Giorgio;
2023

Abstract

Cystic fibrosis (CF) is an autosomal recessive disorder characterized by respiratory failure due to a vicious cycle of defective Cystic Fibrosis Transmembrane conductance Regulator (CFTR) function, chronic inflammation and recurrent bacterial and fungal infections. Although the recent introduction of CFTR correctors/potentiators has revolutionized the clinical management of CF patients, resurgence of inflammation and persistence of pathogens still posit a major concern and should be targeted contextually. On the background of a network-based selectivity that allows to target the same enzyme in the host and microbes with different outcomes, we focused on sphingosine-1-phosphate (S1P) lyase (SPL) of the sphingolipid metabolism as a potential candidate to uniquely induce anti-inflammatory and antifungal activities in CF. As a feasibility study, herein we show that interfering with S1P metabolism improved the immune response in a murine model of CF with aspergillosis while preventing germination of Aspergillus fumigatus conidia. In addition, in an early drug discovery process, we purified human and A. fumigatus SPL, characterized their biochemical and structural properties, and performed an in silico screening to identify potential dual species SPL inhibitors. We identified two hits behaving as competitive inhibitors of pathogen and host SPL, thus paving the way for hit-to-lead and translational studies for the development of drug candidates capable of restraining fungal growth and increasing antifungal resistance.
2023
CF; cystic fibrosis; S1P; sphingosine-1-phosphate ; ceramide; SPL; sphingosine phosphate lyase; PLP; pyridoxal 5′-phosphate; AfuSPL; Aspergillus fumigatus; SPL ; CD; circular dichroism
01 Pubblicazione su rivista::01a Articolo in rivista
Dual species sphingosine-1-phosphate lyase inhibitors to combine antifungal and anti-inflammatory activities in cystic fibrosis: a feasibility study / Cellini, Barbara; Pampalone, Gioena; Camaioni, Emidio; Pariano, Marilena; Catalano, Flavia; Zelante, Teresa; Dindo, Mirco; Macchioni, Lara; Di Veroli, Alessandra; Galarini, Roberta; Paoletti, Fabiola; Davidescu, Magdalena; Stincardini, Claudia; Vascelli, Gianluca; Bellet, Marina Maria; Saba, Julie; Giovagnoli, Stefano; Giardina, Giorgio; Romani, Luigina; Costantini, Claudio. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 13:1(2023), p. 22692. [10.1038/s41598-023-50121-4]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1697907
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