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Targeted Covalent Inhibition of Plasmodium FK506 Binding Protein 35.

ABSTRACT: 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.

SUBMITTER: Atack TC

PROVIDER: S-EPMC7667655 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Targeted Covalent Inhibition of <i>Plasmodium</i> FK506 Binding Protein 35.

Atack Thomas C TC Raymond Donald D DD Blomquist Christa A CA Pasaje Charisse Flerida CF McCarren Patrick R PR Moroco Jamie J Befekadu Henock B HB Robinson Foxy P FP Pal Debjani D Esherick Lisl Y LY Ianari Alessandra A Niles Jacquin C JC Sellers William R WR

ACS medicinal chemistry letters 20200901 11

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, provid ...[more]

PMID: 33209191

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