Structure-guided optimization of small molecules targeting Yck2 as a strategy to combat Candida albicans
Abstract Candida albicans is the most common cause of life-threatening fungal infection in the developed world but remains a therapeutic challenge. Protein kinases have been rewarding drug targets across diverse indications but remain untapped for antifungal development. Previously, screening kinase...
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57346-z |
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| author | Emily Puumala Meganathan Nandakumar Bonnie Yiu Peter J. Stogios Benjamin G. Strickland Robert Zarnowski Xiaoyu Wang Noelle S. Williams Alexei Savchenko David R. Andes Nicole Robbins Luke Whitesell Timothy M. Willson Leah E. Cowen |
| author_facet | Emily Puumala Meganathan Nandakumar Bonnie Yiu Peter J. Stogios Benjamin G. Strickland Robert Zarnowski Xiaoyu Wang Noelle S. Williams Alexei Savchenko David R. Andes Nicole Robbins Luke Whitesell Timothy M. Willson Leah E. Cowen |
| author_sort | Emily Puumala |
| collection | DOAJ |
| description | Abstract Candida albicans is the most common cause of life-threatening fungal infection in the developed world but remains a therapeutic challenge. Protein kinases have been rewarding drug targets across diverse indications but remain untapped for antifungal development. Previously, screening kinase inhibitors against C. albicans revealed a 2,3-aryl-pyrazolopyridine, GW461484A (GW), which targets casein kinase 1 (CK1) family member Yck2. Here, we report optimization of GW via two complementary approaches, synthesis of bioisosteres possessing an imidazo[1,2-a]pyridine core, and R-group substitution of GW’s pyrazolo[1,5-a]pyridine core. Characterization of compounds reveals two 6-cyano derivatives with improved pharmacological properties that retain whole-cell bioactivity and selectivity for fungal Yck2 compared to human CK1α. Efficacy studies in mice indicate both analogs possess single-agent activity against C. albicans resistant to first-line echinocandin antifungals and potentiate non-curative echinocandin treatment. Results validate Yck2 as an antifungal target and encourage further development of inhibitors acting by this previously unexploited mode of action. |
| format | Article |
| id | doaj-art-746af135086e4ba09862bfc8d373c3ab |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-746af135086e4ba09862bfc8d373c3ab2025-08-20T03:05:45ZengNature PortfolioNature Communications2041-17232025-03-0116111610.1038/s41467-025-57346-zStructure-guided optimization of small molecules targeting Yck2 as a strategy to combat Candida albicansEmily Puumala0Meganathan Nandakumar1Bonnie Yiu2Peter J. Stogios3Benjamin G. Strickland4Robert Zarnowski5Xiaoyu Wang6Noelle S. Williams7Alexei Savchenko8David R. Andes9Nicole Robbins10Luke Whitesell11Timothy M. Willson12Leah E. Cowen13Department of Molecular Genetics, University of TorontoStructural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel HillDepartment of Molecular Genetics, University of TorontoDepartment of Chemical Engineering and Applied Chemistry, University of TorontoStructural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel HillDepartment of Medicine, University of Wisconsin-MadisonDepartment of Biochemistry, University of Texas Southwestern Medical SchoolDepartment of Biochemistry, University of Texas Southwestern Medical SchoolDepartment of Chemical Engineering and Applied Chemistry, University of TorontoDepartment of Medicine, University of Wisconsin-MadisonDepartment of Molecular Genetics, University of TorontoDepartment of Molecular Genetics, University of TorontoStructural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel HillDepartment of Molecular Genetics, University of TorontoAbstract Candida albicans is the most common cause of life-threatening fungal infection in the developed world but remains a therapeutic challenge. Protein kinases have been rewarding drug targets across diverse indications but remain untapped for antifungal development. Previously, screening kinase inhibitors against C. albicans revealed a 2,3-aryl-pyrazolopyridine, GW461484A (GW), which targets casein kinase 1 (CK1) family member Yck2. Here, we report optimization of GW via two complementary approaches, synthesis of bioisosteres possessing an imidazo[1,2-a]pyridine core, and R-group substitution of GW’s pyrazolo[1,5-a]pyridine core. Characterization of compounds reveals two 6-cyano derivatives with improved pharmacological properties that retain whole-cell bioactivity and selectivity for fungal Yck2 compared to human CK1α. Efficacy studies in mice indicate both analogs possess single-agent activity against C. albicans resistant to first-line echinocandin antifungals and potentiate non-curative echinocandin treatment. Results validate Yck2 as an antifungal target and encourage further development of inhibitors acting by this previously unexploited mode of action.https://doi.org/10.1038/s41467-025-57346-z |
| spellingShingle | Emily Puumala Meganathan Nandakumar Bonnie Yiu Peter J. Stogios Benjamin G. Strickland Robert Zarnowski Xiaoyu Wang Noelle S. Williams Alexei Savchenko David R. Andes Nicole Robbins Luke Whitesell Timothy M. Willson Leah E. Cowen Structure-guided optimization of small molecules targeting Yck2 as a strategy to combat Candida albicans Nature Communications |
| title | Structure-guided optimization of small molecules targeting Yck2 as a strategy to combat Candida albicans |
| title_full | Structure-guided optimization of small molecules targeting Yck2 as a strategy to combat Candida albicans |
| title_fullStr | Structure-guided optimization of small molecules targeting Yck2 as a strategy to combat Candida albicans |
| title_full_unstemmed | Structure-guided optimization of small molecules targeting Yck2 as a strategy to combat Candida albicans |
| title_short | Structure-guided optimization of small molecules targeting Yck2 as a strategy to combat Candida albicans |
| title_sort | structure guided optimization of small molecules targeting yck2 as a strategy to combat candida albicans |
| url | https://doi.org/10.1038/s41467-025-57346-z |
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