2. Academic Validation
  3. Targeted Covalent Inhibition of Plasmodium FK506 Binding Protein 35

Targeted Covalent Inhibition of Plasmodium FK506 Binding Protein 35

  • ACS Med Chem Lett. 2020 Sep 1;11(11):2131-2138. doi: 10.1021/acsmedchemlett.0c00272.
Thomas C Atack 1,  Donald D Raymond 1,  Christa A Blomquist 1,  Charisse Flerida Pasaje 2,  Patrick R McCarren 1,  Jamie Moroco 1,  Henock B Befekadu 1,  Foxy P Robinson 1,  Debjani Pal 1,  Lisl Y Esherick 2,  Alessandra Ianari 1,  Jacquin C Niles 2,  William R Sellers 1 3 4
Affiliations

Affiliations

  • 1 Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States.
  • 2 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
  • 3 Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, United States.
  • 4 Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, United States.
PMID: 33209191 DOI: 10.1021/acsmedchemlett.0c00272
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.

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