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Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents

Author

Listed:
  • Praveen R. Juvvadi

    (Duke University Medical Center)

  • David Fox

    (Beryllium Discovery Corp.
    UCB Pharma.
    Seattle Structural Genomics Center for Infectious Disease (SSGCID))

  • Benjamin G. Bobay

    (Duke University Medical Center
    Duke University
    Duke University)

  • Michael J. Hoy

    (Duke University Medical Center)

  • Sophie M. C. Gobeil

    (Duke University
    Duke University)

  • Ronald A. Venters

    (Duke University Medical Center
    Duke University
    Duke University)

  • Zanetta Chang

    (Duke University Medical Center)

  • Jackie J. Lin

    (Duke University Medical Center)

  • Anna Floyd Averette

    (Duke University Medical Center)

  • D. Christopher Cole

    (Duke University Medical Center)

  • Blake C. Barrington

    (Duke University Medical Center)

  • Joshua D. Wheaton

    (Duke University Medical Center)

  • Maria Ciofani

    (Duke University Medical Center)

  • Michael Trzoss

    (Amplyx Pharmaceuticals)

  • Xiaoming Li

    (Amplyx Pharmaceuticals
    Forge Therapeutics, Inc.)

  • Soo Chan Lee

    (The University of Texas at San Antonio)

  • Ying-Lien Chen

    (National Taiwan University)

  • Mitchell Mutz

    (Amplyx Pharmaceuticals
    Genentech Inc.)

  • Leonard D. Spicer

    (Duke University Medical Center
    Duke University
    Duke University)

  • Maria A. Schumacher

    (Duke University)

  • Joseph Heitman

    (Duke University Medical Center)

  • William J. Steinbach

    (Duke University Medical Center
    Duke University Medical Center)

Abstract

Calcineurin is important for fungal virulence and a potential antifungal target, but compounds targeting calcineurin, such as FK506, are immunosuppressive. Here we report the crystal structures of calcineurin catalytic (CnA) and regulatory (CnB) subunits complexed with FK506 and the FK506-binding protein (FKBP12) from human fungal pathogens (Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans and Coccidioides immitis). Fungal calcineurin complexes are similar to the mammalian complex, but comparison of fungal and human FKBP12 (hFKBP12) reveals conformational differences in the 40s and 80s loops. NMR analysis, molecular dynamic simulations, and mutations of the A. fumigatus CnA/CnB-FK506-FKBP12-complex identify a Phe88 residue, not conserved in hFKBP12, as critical for binding and inhibition of fungal calcineurin. These differences enable us to develop a less immunosuppressive FK506 analog, APX879, with an acetohydrazine substitution of the C22-carbonyl of FK506. APX879 exhibits reduced immunosuppressive activity and retains broad-spectrum antifungal activity and efficacy in a murine model of invasive fungal infection.

Suggested Citation

  • Praveen R. Juvvadi & David Fox & Benjamin G. Bobay & Michael J. Hoy & Sophie M. C. Gobeil & Ronald A. Venters & Zanetta Chang & Jackie J. Lin & Anna Floyd Averette & D. Christopher Cole & Blake C. Bar, 2019. "Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12199-1
    DOI: 10.1038/s41467-019-12199-1
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