https://scholars.lib.ntu.edu.tw/handle/123456789/565917
標題: | Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents | 作者: | Juvvadi, P.R. Fox, D. Bobay, B.G. Hoy, M.J. Gobeil, S.M.C. Venters, R.A. Chang, Z. Lin, J.J. Averette, A.F. Cole, D.C. Barrington, B.C. Wheaton, J.D. Ciofani, M. Trzoss, M. Li, X. Lee, S.C. YING-LIEN CHEN Mutz, M. Spicer, L.D. Schumacher, M.A. Heitman, J. Steinbach, W.J. |
公開日期: | 2019 | 卷: | 10 | 期: | 1 | 來源出版物: | Nature Communications | 摘要: | 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. ? 2019, The Author(s). |
URI: | https://www.scopus.com/inward/record.url?eid=2-s2.0-85072391216&partnerID=40&md5=a9f8525d24fc1e9d95b5c8c4da0e98c9 https://scholars.lib.ntu.edu.tw/handle/123456789/565917 |
DOI: | 10.1038/s41467-019-12199-1 | SDG/關鍵字: | antifungal agent; APX879; calcineurin; cyclophosphamide; fk 506 binding protein; fluconazole; tacrolimus; triamcinolone; unclassified drug; antifungal agent; calcineurin; calcineurin inhibitor; fk 506 binding protein; tacrolimus; crystal structure; disease treatment; fungal disease; fungus; inhibition; molecular analysis; mutation; protein; virulence; animal cell; animal experiment; animal model; animal tissue; antifungal activity; antifungal susceptibility; Article; aspergillosis; Aspergillus fumigatus; Candida albicans; cell culture; CFU counting; Coccidioides immitis; controlled study; Cryptococcus neoformans; crystal structure; DNA sequence; drug efficacy; drug synthesis; female; flow cytometry; fluorescence microscopy; fungus; gene mutation; genetic transfection; immunosuppressive treatment; infectious agent; invasive candidiasis; male; minimum inhibitory concentration; molecular docking; molecular dynamics; molecular model; mouse; mucormycosis; nonhuman; nuclear magnetic resonance; polymerase chain reaction; protein conformation; protein expression; protein isolation; protein purification; single drug dose; site directed mutagenesis; size exclusion chromatography; Western blotting; X ray crystallography; A J mouse; animal; aspergillosis; binding site; C57BL mouse; Coccidioides; cryptococcosis; drug development; drug effect; metabolism; microbiology; procedures; Aspergillus fumigatus; Candida albicans; Coccidioides immitis; Filobasidiella neoformans; Mammalia; Murinae; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Binding Sites; Calcineurin; Calcineurin Inhibitors; Candida albicans; Cells, Cultured; Coccidioides; Cryptococcosis; Cryptococcus neoformans; Crystallography, X-Ray; Drug Discovery; Female; Male; Mice; Mice, Inbred A; Mice, Inbred C57BL; Molecular Dynamics Simulation; Tacrolimus; Tacrolimus Binding Protein 1A |
顯示於: | 植物病理與微生物學系 |
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