Reverse Chemical Proteomics Identifies an Unanticipated Human Target of the Antimalarial Artesunate

Michael P. Gotsbacher, Sung Min Cho, Nam Hee Kim, Fei Liu, Ho Jeong Kwon, Peter Karuso

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Artemisinins are the most potent and safe antimalarials available. Despite their clinical potential, no human target for the artemisinins is known. The unbiased interrogation of several human cDNA libraries, displayed on bacteriophage T7, revealed a single human target of artesunate; the intrinsically disordered Bcl-2 antagonist of cell death promoter (BAD). We show that artesunate inhibits the phosphorylation of BAD, thereby promoting the formation of the proapoptotic BAD/Bcl-xL complex and the subsequent intrinsic apoptotic cascade involving cytochrome c release, PARP cleavage, caspase activation, and ultimately cell death. This unanticipated role of BAD as a possible drug target of artesunate points to direct clinical exploitation of artemisinins in the Bcl-xL life/death switch and that artesunate's anticancer activity is, at least in part, independent of reactive oxygen species.

Original languageEnglish
Pages (from-to)636-643
Number of pages8
JournalACS Chemical Biology
Volume14
Issue number4
DOIs
Publication statusPublished - 2019 Apr 19

Fingerprint

Artemisinins
Antimalarials
Proteomics
Cell death
Cell Death
Bacteriophage T7
Phosphorylation
Bacteriophages
Caspases
Cytochromes c
Gene Library
Reactive Oxygen Species
Chemical activation
Switches
artesunate
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine

Cite this

Gotsbacher, Michael P. ; Cho, Sung Min ; Kim, Nam Hee ; Liu, Fei ; Kwon, Ho Jeong ; Karuso, Peter. / Reverse Chemical Proteomics Identifies an Unanticipated Human Target of the Antimalarial Artesunate. In: ACS Chemical Biology. 2019 ; Vol. 14, No. 4. pp. 636-643.
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Reverse Chemical Proteomics Identifies an Unanticipated Human Target of the Antimalarial Artesunate. / Gotsbacher, Michael P.; Cho, Sung Min; Kim, Nam Hee; Liu, Fei; Kwon, Ho Jeong; Karuso, Peter.

In: ACS Chemical Biology, Vol. 14, No. 4, 19.04.2019, p. 636-643.

Research output: Contribution to journalArticle

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