Article ; Online: Leveraging Fungal and Human Calcineurin-Inhibitor Structures, Biophysical Data, and Dynamics To Design Selective and Nonimmunosuppressive FK506 Analogs.
2021 Volume 12, Issue 6, Page(s) e0300021
Abstract: Calcineurin is a critical enzyme in fungal pathogenesis and antifungal drug tolerance and, therefore, an attractive antifungal target. Current clinically accessible calcineurin inhibitors, such as FK506, are immunosuppressive to humans, so exploiting ... ...
Abstract | Calcineurin is a critical enzyme in fungal pathogenesis and antifungal drug tolerance and, therefore, an attractive antifungal target. Current clinically accessible calcineurin inhibitors, such as FK506, are immunosuppressive to humans, so exploiting calcineurin inhibition as an antifungal strategy necessitates fungal specificity in order to avoid inhibiting the human pathway. Harnessing fungal calcineurin-inhibitor crystal structures, we recently developed a less immunosuppressive FK506 analog, APX879, with broad-spectrum antifungal activity and demonstrable efficacy in a murine model of invasive fungal infection. Our overarching goal is to better understand, at a molecular level, the interaction determinants of the human and fungal FK506-binding proteins (FKBP12) required for calcineurin inhibition in order to guide the design of fungus-selective, nonimmunosuppressive FK506 analogs. To this end, we characterized high-resolution structures of the Mucor circinelloides FKBP12 bound to FK506 and of the Aspergillus fumigatus, |
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MeSH term(s) | Amino Acid Sequence ; Antifungal Agents/chemistry ; Antifungal Agents/pharmacology ; Calcineurin/chemistry ; Calcineurin/genetics ; Calcineurin/metabolism ; Calcineurin Inhibitors/chemistry ; Calcineurin Inhibitors/pharmacology ; Drug Design ; Fungal Proteins/chemistry ; Fungal Proteins/genetics ; Fungal Proteins/metabolism ; Host-Pathogen Interactions ; Humans ; Mucor/drug effects ; Mucor/genetics ; Mucor/metabolism ; Mucormycosis/drug therapy ; Mucormycosis/genetics ; Mucormycosis/metabolism ; Mucormycosis/microbiology ; Sequence Alignment ; Tacrolimus/chemistry ; Tacrolimus/pharmacology ; Tacrolimus Binding Protein 1A/chemistry ; Tacrolimus Binding Protein 1A/genetics ; Tacrolimus Binding Protein 1A/metabolism |
Chemical Substances | Antifungal Agents ; Calcineurin Inhibitors ; Fungal Proteins ; Calcineurin (EC 3.1.3.16) ; Tacrolimus Binding Protein 1A (EC 5.2.1.-) ; Tacrolimus (WM0HAQ4WNM) |
Language | English |
Publishing date | 2021-11-23 |
Publishing country | United States |
Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. |
ZDB-ID | 2557172-2 |
ISSN | 2150-7511 ; 2161-2129 |
ISSN (online) | 2150-7511 |
ISSN | 2161-2129 |
DOI | 10.1128/mBio.03000-21 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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