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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Wright, MB; Varona Santos, J; Kemmer, C; Maugeais, C; Carralot, J-P; Roever, S; Molina, J; Ducasa, GM; Mitrofanova, A; Sloan, A; Ahmad, A; Pedigo, C; Ge, M; Pressly, J; Barisoni, L; Mendez, A; Sgrignani, J; Cavalli, A; Merscher, S; Prunotto, M; Fornoni, A

Published Date

  • August 2, 2021

Published In

Volume / Issue

  • 12 / 1

Start / End Page

  • 4662 -

PubMed ID

  • 34341345

Pubmed Central ID

  • PMC8329197

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-021-24890-3


  • eng

Conference Location

  • England