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

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. Barrington, Joshua D. Wheaton, Maria Ciofani, Michael Trzoss, Xiaoming Li, Soo Chan Lee, Ying-Lien Chen, Mitchell Mutz, Leonard D. Spicer, Maria A. Schumacher, Joseph Heitman and William J. Steinbach ()
Additional contact information
Praveen R. Juvvadi: Duke University Medical Center
David Fox: Beryllium Discovery Corp.
Benjamin G. Bobay: Duke University Medical Center
Michael J. Hoy: Duke University Medical Center
Sophie M. C. Gobeil: Duke University
Ronald A. Venters: Duke University Medical Center
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
Soo Chan Lee: The University of Texas at San Antonio
Ying-Lien Chen: National Taiwan University
Mitchell Mutz: Amplyx Pharmaceuticals
Leonard D. Spicer: Duke University Medical Center
Maria A. Schumacher: Duke University
Joseph Heitman: Duke University Medical Center
William J. Steinbach: Duke University Medical Center

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12199-1

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