Promiscuous targeting of antimalarial artemisinin

23 Dec 2015 NUS scientists systematically identified over 120 targets of artemisinin and unveiled its haem-dependent drug activation and potent parasite killing mechanism.

Malaria is a mosquito-borne infectious disease that causes over half-a-million deaths each year. Artemisinin is currently the most potent anti-malarial drug and is considered our ‘last line of defense against malaria’. The Chinese Scientist Youyou Tu who discovered this drug has just been awarded the Nobel Prize. Being such an important drug, however, its mechanism was still not so well understood. A team led by Dr. LIN Qingsong and Dr. WANG Jigang from the Department of Biological Sciences in NUS, together with Prof Kevin S.W. TAN from the Department of Microbiology and Immunology in NUS identify 124 protein targets of artemisinin, revealing its potent parasite killing effect through promiscuously targeting multiple essential biological pathways. They also demonstrated that artemisinin activation requires the iron containing cofactor, haem, either biosynthesized by the parasite at its early developmental ring stage, or derived from haemoglobin digestion in the later stages (see Figure).

Previously only two targets of artemisinin have been identified, and their correlation with the powerful parasite killing effect of the drug has been questioned. The current identification of multiple targets provides a sound explanation of the mechanism of action of the drug. This knowledge will facilitate the development of new drugs and therapeutic strategies against malaria. The artemisinin resistance emerging in Southeast Asia is due to enhanced stress response in the ring-stage parasites. The current finding that artemisinin activation in the ring-stage parasites relies on haem biosynthesis may pave a new way to overcome drug resistance through enhancing the haem biosynthesis and/or prolonging the drug treatment at ring stage.

The next step of this research will be to understand how the drug interacts with the targets through structural biology and physicochemical approaches, and to explore the feasibility of enhancing the killing of artemisinin-resistant parasite strains through manipulating the haem biosynthesis at the early ring stage of the parasites. Novel artemisinin analogues with more specific targeting properties are also under development through collaboration with researchers in the Department of Chemical and Biomolecular Engineering in NUS.

Artemisinin, activated by haem, effectively kills the malaria parasites by covalently targeting over 120 proteins [Image credit: Wang Jigang].

Reference

Wang JG, Zhang CJ, Chia W, Loh CCY, Li ZJ, Lee YQ, Lee YM, He YK, Yuan LX, Liu M, Liew CX, Zhang JB, Lim TK, Lu NC, Lim CT, Shen HM, Tan KSW, Lin QS. “Heme-activated Promiscuous Targeting of Artemisinin in Plasmodium falciparum.” Nature Communications 6 (2015) 10111 DOI: 10.1038/ncomms10111.