Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 11, Issue 11, Pages 2131-2138Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00272
Keywords
FK506-binding protein; FKBP35; plasmodium; antimalarial; targeted covalent inhibition
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Funding
- NIEHS NIH HHS [T32 ES007020] Funding Source: Medline
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FK506-binding protein 35, FKBP35, has been implicated as an essential malarial enzyme. Rapamycin and FK506 exhibit antiplasmodium activity in cultured parasites. However, due to the highly conserved nature of the binding pockets of FKBPs and the immunosuppressive properties of these drugs, there is a need for compounds that selectively inhibit FKBP35 and lack the undesired side effects. In contrast to human FKBPs, FKBP35 contains a cysteine, C106, adjacent to the rapamycin binding pocket, providing an opportunity to develop targeted covalent inhibitors of Plasmodium FKBP35. Here, we synthesize inhibitors of FKBP35, show that they directly bind FKBP35 in a model cellular setting, selectively covalently modify C106, and exhibit antiplasmodium activity in blood-stage cultured parasites.
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