Compounds targeting OSBPL7 increase ABCA1-dependent cholesterol efflux preserving kidney function in two models of kidney disease

Matthew B. Wright, Javier Varona Santos, Christian Kemmer, Cyrille Maugeais, Jean-Philippe Carralot, Stephan Roever, Judith Molina, G. Michelle Ducasa, Alla Mitrofanova, Alexis Sloan, Anis Ahmad, Christopher Pedigo, Mengyuan Ge, Jeffrey Pressly, Laura Barisoni, Armando Mendez, Jacopo Sgrignani, Andrea Cavalli, Sandra Merscher, Marco Prunotto () and Alessia Fornoni ()
Additional contact information
Matthew B. Wright: F. Hoffmann-La Roche Ltd
Javier Varona Santos: University of Miami, Miller School of Medicine
Christian Kemmer: F. Hoffmann-La Roche Ltd
Cyrille Maugeais: F. Hoffmann-La Roche Ltd
Jean-Philippe Carralot: F. Hoffmann-La Roche Ltd
Stephan Roever: F. Hoffmann-La Roche Ltd
Judith Molina: University of Miami, Miller School of Medicine
G. Michelle Ducasa: University of Miami, Miller School of Medicine
Alla Mitrofanova: University of Miami, Miller School of Medicine
Alexis Sloan: University of Miami, Miller School of Medicine
Anis Ahmad: University of Miami, Miller School of Medicine
Christopher Pedigo: University of Miami, Miller School of Medicine
Mengyuan Ge: University of Miami, Miller School of Medicine
Jeffrey Pressly: University of Miami, Miller School of Medicine
Laura Barisoni: University of Miami, Miller School of Medicine
Armando Mendez: University of Miami, Miller School of Medicine
Jacopo Sgrignani: Università della Svizzera Italiana
Andrea Cavalli: Università della Svizzera Italiana
Sandra Merscher: University of Miami, Miller School of Medicine
Marco Prunotto: F. Hoffmann-La Roche Ltd
Alessia Fornoni: University of Miami, Miller School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Impaired cellular cholesterol efflux is a key factor in the progression of renal, cardiovascular, and autoimmune diseases. Here we describe a class of 5-arylnicotinamide compounds, identified through phenotypic drug discovery, that upregulate ABCA1-dependent cholesterol efflux by targeting Oxysterol Binding Protein Like 7 (OSBPL7). OSBPL7 was identified as the molecular target of these compounds through a chemical biology approach, employing a photoactivatable 5-arylnicotinamide derivative in a cellular cross-linking/immunoprecipitation assay. Further evaluation of two compounds (Cpd A and Cpd G) showed that they induced ABCA1 and cholesterol efflux from podocytes in vitro and normalized proteinuria and prevented renal function decline in mouse models of proteinuric kidney disease: Adriamycin-induced nephropathy and Alport Syndrome. In conclusion, we show that small molecule drugs targeting OSBPL7 reveal an alternative mechanism to upregulate ABCA1, and may represent a promising new therapeutic strategy for the treatment of renal diseases and other disorders of cellular cholesterol homeostasis.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24890-3

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DOI: 10.1038/s41467-021-24890-3

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