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

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

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. marco.prunotto@unige.ch.
  • 11 School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland. marco.prunotto@unige.ch.
  • 12 Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA. afornoni@med.miami.edu.
  • 13 Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA. afornoni@med.miami.edu.
  • # 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.

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