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

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

doi:10.1038/s41467-019-12199-1

Cited by 82 publications

(121 citation statements)

References 56 publications

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“…2), consistent with previous analysis using hFKBP12 20 . Using structure and sequence alignments, a single mutation of hFKBP12-His88 to Phe (AfFKBP12 identity), was shown to restore FK506 sensitivity 20 . Interestingly, in McFKBP12 residue 88 is a Tyr, potentially sterically hindering the ternary complex formation with A. fumigatus calcineurin.…”

Section: Growth Assays In the Presence Of Increasing Concentrations Osupporting

confidence: 92%

“…3A and Supplementary Fig. 2), consistent with previous analysis using hFKBP12 20 . Using structure and sequence alignments, a single mutation of hFKBP12-His88 to Phe (AfFKBP12 identity), was shown to restore FK506 sensitivity 20 .…”

Section: Growth Assays In the Presence Of Increasing Concentrations Osupporting

confidence: 91%

“…We proposed that APX879 would interact less favorably with the human FKBP12 (hFKBP12) His88 residue than with the corresponding A. fumigatus FKBP12 (AfFKBP12) Phe88 residue thus, potentially reducing immunosuppression 20 . APX879 displayed a 71-fold reduced immunosuppressive activity compared to FK506 while maintaining broadspectrum in vitro antifungal activity against a wide range of human pathogenic fungi 20 . In vivo testing in murine model confirmed reduced immunosuppressive activity, and efficacy in a Cryptococcal model of invasive fungal infection 20 .…”

mentioning

confidence: 99%

“…APX879 displayed a 71-fold reduced immunosuppressive activity compared to FK506 while maintaining broadspectrum in vitro antifungal activity against a wide range of human pathogenic fungi 20 . In vivo testing in murine model confirmed reduced immunosuppressive activity, and efficacy in a Cryptococcal model of invasive fungal infection 20 .…”

mentioning

confidence: 99%

“…Here, we report the first high-resolution crystal structures of McFKBP12 bound to FK506 in addition to the hFKBP12, AfFKBP12, and McFKBP12 proteins bound to APX879 20 . Through genetic studies, we demonstrate that McFKBP12 does not functionally complement AfFKBP12 and reveal key requirements of FKBP12 residue 88 for productive binding and inhibition of calcineurin.…”

mentioning

confidence: 99%

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Leveraging Fungal Calcineurin-Inhibitor Structures, Biophysics and Dynamics to Design Selective and Non-Immunosuppressive FK506 Analogs

Gobeil

Bobay

Juvvadi

et al. 2020

Preprint

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Calcineurin is an attractive antifungal target due to its central role in fungal pathogenesis. The development of specific antifungals targeting calcineurin is complex, as calcineurin inhibitors, such as FK506, are immunosuppressive. Using fungal calcineurin-inhibitor crystal structures we recently developed a less immunosuppressive FK506 analog, APX879, with broad-spectrum antifungal activity and efficacy in a murine model of invasive fungal infection. To better understand the interaction of the human and fungal FK506-binding proteins (FKBP12) required for calcineurin inhibition at a molecular level, and guide the design of fungal-selective and nonimmunosuppressive FK506 analogs, here we report the high-resolution structures of the M. circinelloides FKBP12 bound to FK506 and the human, A. fumigatus and M. circinelloides FKBP12 proteins bound to the FK506 analog, APX879. Combining structural, genetic and biophysical methodologies with molecular dynamics simulations, we identify critical variations in these structurally similar FKBP12:ligand complexes to enhance fungal-selectivity.

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Section: Growth Assays In the Presence Of Increasing Concentrations Osupporting

confidence: 92%

Section: Growth Assays In the Presence Of Increasing Concentrations Osupporting

confidence: 91%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Leveraging Fungal Calcineurin-Inhibitor Structures, Biophysics and Dynamics to Design Selective and Non-Immunosuppressive FK506 Analogs

Gobeil

Bobay

Juvvadi

et al. 2020

Preprint

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Spectroscopic studies, antimicrobial activity, and computational investigations of hydrazone ligands endowed metal chelates

Arora,

Devi,

Dubey

et al. 2023

Applied Organom Chemis

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Our current efforts are aimed to synthesize 16 complexes of Co (II), Ni (II), Cu (II), and Zn (II) metal ions from heterocyclic hydrazone ligands by condensation reaction of 2,6‐diacetylpyridine with hydrazide derivatives to find out combating agent against microorganism diseases. The synthesized compounds were precisely characterized by various physicochemical and spectroscopic techniques like FT‐IR, UV–Vis, 1H and 13C NMR, magnetic susceptibility, ESR, mass spectrometry, powder XRD, TGA, and SEM that suggested the octahedral geometry of the complexes coordinating via enolic oxygen atoms, azomethine nitrogen atom, pyridine ring nitrogen atom of the hydrazone ligands, and oxygen atom of water molecule. The thermal stability of the complexes was demonstrated by thermal analysis revealing two‐step decompositions leaving behind metal oxide as an end residue. By using serial dilution method, the compounds (1–20) were tested for in vitro antimicrobial activity against four bacterial and two fungal pathogens. Among all the synthesized compounds, complex 16 was most active against B. subtilis, whereas complexes 13, 14, and 15 were most efficient for C. albicans. Moreover, the biological efficacy of H2L3 (3) ligand and its (13–16) complexes were demonstrated by computational methods like molecular docking, MESP, DFT, and ADMET studies that highlight that complexes have more potency than the ligands and may be employed as effective drug for pathogen‐induced malformations.

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Generation of Bioactivity‐Tailored FK506/FK520 Analogs by CRISPR Editing in Streptomyces tsukubaensis

Buntin,

Mrak,

Pivk Lukančič

et al. 2023

Chemistry A European J

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For a potential application of FK506 in the treatment of acute kidney failure only the FKBP12 binding capability of the compound is required while the immunosuppressive activity via calcineurin binding is considered as a likely risk to the patients. The methoxy‐groups at C13 and C15 are thought to have significant influence on the immunosuppressive activity of the molecule. Consequently, FK506 analogs with different functionalities at C13 and C15 were generated by targeted CRISPR editing of the AT domains in module 7 and 8 of the biosynthetic assembly line in Streptomyces tsukubaensis. In addition, the corresponding FK520 (C21 ethyl derivative of FK506) analogs could be obtained by media adjustments. The compounds were tested for their bioactivity in regards to FKBP12 binding, BMP potentiation and calcineurin sparing. 15‐desmethoxy FK506 was superior to the other tested analogs as it did not inhibit calcineurin but retained high potency towards FKBP12 binding and BMP potentiation.

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

Cited by 82 publications

References 56 publications

Leveraging Fungal Calcineurin-Inhibitor Structures, Biophysics and Dynamics to Design Selective and Non-Immunosuppressive FK506 Analogs

Leveraging Fungal Calcineurin-Inhibitor Structures, Biophysics and Dynamics to Design Selective and Non-Immunosuppressive FK506 Analogs

Spectroscopic studies, antimicrobial activity, and computational investigations of hydrazone ligands endowed metal chelates

Generation of Bioactivity‐Tailored FK506/FK520 Analogs by CRISPR Editing in Streptomyces tsukubaensis

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