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

Publication ,  Journal Article
Wright, MB; Varona Santos, J; Kemmer, C; Maugeais, C; Carralot, J-P; Roever, S; Molina, J; Ducasa, GM; Mitrofanova, A; Sloan, A; Ahmad, A ...
Published in: Nat Commun
August 2, 2021

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.

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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

August 2, 2021

Volume

12

Issue

1

Start / End Page

4662

Location

England

Related Subject Headings

  • THP-1 Cells
  • Receptors, Steroid
  • RNA Interference
  • Proteinuria
  • Podocytes
  • Organic Chemicals
  • Niacinamide
  • Molecular Structure
  • Mice, Knockout
  • Mice, 129 Strain
 

Citation

APA
Chicago
ICMJE
MLA
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Wright, M. B., Varona Santos, J., Kemmer, C., Maugeais, C., Carralot, J.-P., Roever, S., … Fornoni, A. (2021). Compounds targeting OSBPL7 increase ABCA1-dependent cholesterol efflux preserving kidney function in two models of kidney disease. Nat Commun, 12(1), 4662. https://doi.org/10.1038/s41467-021-24890-3
Wright, Matthew B., Javier Varona Santos, Christian Kemmer, Cyrille Maugeais, Jean-Philippe Carralot, Stephan Roever, Judith Molina, et al. “Compounds targeting OSBPL7 increase ABCA1-dependent cholesterol efflux preserving kidney function in two models of kidney disease.Nat Commun 12, no. 1 (August 2, 2021): 4662. https://doi.org/10.1038/s41467-021-24890-3.
Wright MB, Varona Santos J, Kemmer C, Maugeais C, Carralot J-P, Roever S, et al. Compounds targeting OSBPL7 increase ABCA1-dependent cholesterol efflux preserving kidney function in two models of kidney disease. Nat Commun. 2021 Aug 2;12(1):4662.
Wright, Matthew B., et al. “Compounds targeting OSBPL7 increase ABCA1-dependent cholesterol efflux preserving kidney function in two models of kidney disease.Nat Commun, vol. 12, no. 1, Aug. 2021, p. 4662. Pubmed, doi:10.1038/s41467-021-24890-3.
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. Compounds targeting OSBPL7 increase ABCA1-dependent cholesterol efflux preserving kidney function in two models of kidney disease. Nat Commun. 2021 Aug 2;12(1):4662.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

August 2, 2021

Volume

12

Issue

1

Start / End Page

4662

Location

England

Related Subject Headings

  • THP-1 Cells
  • Receptors, Steroid
  • RNA Interference
  • Proteinuria
  • Podocytes
  • Organic Chemicals
  • Niacinamide
  • Molecular Structure
  • Mice, Knockout
  • Mice, 129 Strain