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 language | English |
|---|---|
| Pages (from-to) | 636-643 |
| Number of pages | 8 |
| Journal | ACS Chemical Biology |
| Volume | 14 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2019 Apr 19 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Molecular Medicine
Cite this
}
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 journal › Article
TY - JOUR
T1 - Reverse Chemical Proteomics Identifies an Unanticipated Human Target of the Antimalarial Artesunate
AU - Gotsbacher, Michael P.
AU - Cho, Sung Min
AU - Kim, Nam Hee
AU - Liu, Fei
AU - Kwon, Ho Jeong
AU - Karuso, Peter
PY - 2019/4/19
Y1 - 2019/4/19
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85063419936&partnerID=8YFLogxK
U2 - 10.1021/acschembio.8b01004
DO - 10.1021/acschembio.8b01004
M3 - Article
C2 - 30840434
AN - SCOPUS:85063419936
VL - 14
SP - 636
EP - 643
JO - ACS Chemical Biology
JF - ACS Chemical Biology
SN - 1554-8929
IS - 4
ER -