Targeted Covalent Inhibition of Plasmodium FK506 Binding Protein 35
Name
acsmedchemlett.0c00272.pdf
Description
Published version
Size
2.35 MB
Format
Unknown
Checksum (MD5)
20c9cff8175d399643cba088848c1396
Author(s)
Atack, Thomas C
Raymond, Donald D
Blomquist, Christa A
Pasaje, Charisse Flerida A
McCarren, Patrick R
Moroco, Jamie
Befekadu, Henock B
Robinson, Foxy P
Pal, Debjani
Esherick, Lisl Y.
Date Issued
September 2020
Journal
ACS Medicinal Chemistry Letters
Publisher
American Chemical Society (ACS)
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1021/ACSMEDCHEMLETT.0C00272
