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

Juvvadi, Praveen R.; Fox, III, David; Bobay, Benjamin G.; Hoy, Michael J.; Gobeil, Sophie M. C.; Venters, Ronald A.; Chang, Zanetta; Lin, Jackie J.; Averette, Anna Floyd; Cole, D. Christopher; Barrington, Blake C.; Wheaton, Joshua D.; Ciofani, Maria; Trzoss, Michael; Li, Xiaoming; Lee, Soo Chan; Chen, Ying-Lien; Mutz, Mitchell; Spicer, Leonard D.; Schumacher, Maria A.; Heitman, Joseph; Steinbach, William J.

doi:10.1038/s41467-019-12199-1

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

Journal Article · Thu Sep 19 00:00:00 EDT 2019 · Nature Communications

DOI:https://doi.org/10.1038/s41467-019-12199-1· OSTI ID:1573396

Juvvadi, Praveen R. ^[1]; Fox, III, David ^[2]; Bobay, Benjamin G. ^[1]; Hoy, Michael J. ^[1];

^[3]; Venters, Ronald A. ^[1]; Chang, Zanetta ^[1]; Lin, Jackie J. ^[1]; Averette, Anna Floyd ^[1]; Cole, D. Christopher ^[1]; Barrington, Blake C. ^[1];

^[1];

^[1]; Trzoss, Michael ^[4]; Li, Xiaoming ^[5];

^[6];

^[7]; Mutz, Mitchell ^[8]; Spicer, Leonard D. ^[1]; Schumacher, Maria A. ^[3] more »

Duke Univ., Durham, NC (United States). Medical Center
Beryllium Discovery Corporation, Bainbridge Island, WA (United States); UCB Pharma., Bainbridge Island, WA (United States); Seattle Structural Genomics Center for Infectious Disease (SSGCID), Seattle, WA (United States)
Duke Univ., Durham, NC (United States)
Amplyx Pharmaceuticals, San Diego, CA (United States)
Amplyx Pharmaceuticals, San Diego, CA (United States); Forge Therapeutics, Inc., San Diego, CA (United States)
Univ. of Texas at San Antonio, TX (United States)
National Taiwan Univ., Taipei (Taiwan)
Amplyx Pharmaceuticals, San Diego, CA (United States); Genentech, San Francisco, CA (United States)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); Ministry of Trade, Industry and Energy (MOTIE) of the Republic of Korea; Michigan Economic Development Corporation; Michigan Technology Tri-Corridor; Canada Foundation for Innovation; Natural Sciences and Engineering Research Council of Canada (NSERC); University of Saskatchewan; Government of Saskatchewan; Western Economic Diversification Canada; National Research Council Canada; Canadian Institutes of Health Research

Grant/Contract Number:: AC02-06CH11357; R01 AI112595-04; P01 AI104533-04; R43AI098300; R43AI106235; N0001720; HHSN272200700057; HHSN272201200025C; HHSN272201700059C; 085P1000817

OSTI ID:: 1573396

Journal Information:: Nature Communications, Vol. 10, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 53 works

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

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