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

• Published in: ACS chemical biology Vol. 14; no. 4; pp. 636 - 643
• Main Authors: Gotsbacher, Michael P, Cho, Sung Min, Kim, Nam Hee, Liu, Fei, Kwon, Ho Jeong, Karuso, Peter
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 19.04.2019
• Subjects: Amino Acid Sequence; Antimalarials - pharmacology; Artesunate - pharmacology; bcl-Associated Death Protein - chemistry; bcl-Associated Death Protein - metabolism; HeLa Cells; Humans; Phosphorylation; Proteomics; Sequence Homology, Amino Acid
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.8b01004

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.