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 PrunottoAlessia Fornoni

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Article number4662
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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