IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-24890-3.html
   My bibliography  Save this article

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

Author

Listed:
  • Matthew B. Wright

    (F. Hoffmann-La Roche Ltd)

  • Javier Varona Santos

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • Christian Kemmer

    (F. Hoffmann-La Roche Ltd)

  • Cyrille Maugeais

    (F. Hoffmann-La Roche Ltd)

  • Jean-Philippe Carralot

    (F. Hoffmann-La Roche Ltd)

  • Stephan Roever

    (F. Hoffmann-La Roche Ltd)

  • Judith Molina

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • G. Michelle Ducasa

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine
    University of Miami Miller School of Medicine)

  • Alla Mitrofanova

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • Alexis Sloan

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • Anis Ahmad

    (University of Miami, Miller School of Medicine)

  • Christopher Pedigo

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • Mengyuan Ge

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • Jeffrey Pressly

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • Laura Barisoni

    (University of Miami, Miller School of Medicine)

  • Armando Mendez

    (University of Miami, Miller School of Medicine)

  • Jacopo Sgrignani

    (Università della Svizzera Italiana)

  • Andrea Cavalli

    (Università della Svizzera Italiana
    Swiss Institute of Bioinformatics)

  • Sandra Merscher

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

  • Marco Prunotto

    (F. Hoffmann-La Roche Ltd
    University of Geneva)

  • Alessia Fornoni

    (University of Miami, Miller School of Medicine
    University of Miami, Miller School of Medicine)

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.

Suggested Citation

  • 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 A, 2021. "Compounds targeting OSBPL7 increase ABCA1-dependent cholesterol efflux preserving kidney function in two models of kidney disease," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24890-3
    DOI: 10.1038/s41467-021-24890-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-24890-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-24890-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24890-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.