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. doi: 10.1038/s41467-021-24890-3.
Matthew B Wright   #  1 ,  Javier Varona Santos   #  2  3 ,  Christian Kemmer  1 ,  Cyrille Maugeais  1 ,  Jean-Philippe Carralot  1 ,  Stephan Roever  1 ,  Judith Molina  2  3 ,  G Michelle Ducasa  2  3  4 ,  Alla Mitrofanova  2  3 ,  Alexis Sloan  2  3 ,  Anis Ahmad  5 ,  Christopher Pedigo  2  3 ,  Mengyuan Ge  2  3 ,  Jeffrey Pressly  2  3 ,  Laura Barisoni  6 ,  Armando Mendez  7 ,  Jacopo Sgrignani  8 ,  Andrea Cavalli  8  9 ,  Sandra Merscher  2  3 ,  Marco Prunotto  10  11 ,  Alessia Fornoni  12  13
Affiliations
  • 1. Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
  • 2. Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA.
  • 3. Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA.
  • 4. Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 5. Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA.
  • 6. Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL, USA.
  • 7. Diabetes Research Institute, University of Miami, Miller School of Medicine, Miami, FL, USA.
  • 8. Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.
  • 9. Swiss Institute of Bioinformatics, Lausanne, Switzerland.
  • 10. Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland. [email protected].
  • 11. School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland. [email protected].
  • 12. Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA. [email protected].
  • 13. Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA. [email protected].
  • # Contributed equally.
PMID: 34341345 DOI: 10.1038/s41467-021-24890-3
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.

Products