HONG KONG — A study by scientists at the National University of Singapore (NUS) has identified more than 100 proteins that are actively targeted by artemisinin in the malarial parasite Plasmodium falciparum, which explains why artemisinin is such an effective antimalarial drug and could facilitate the development of urgently needed effective malaria treatment strategies.
The most pathogenic of the human malaria parasites, P. falciparum infects millions of humans and poses a serious public health threat. Artemisinin is currently the most effective drug available against malaria, with combination therapies based on artemisinin and its derivatives being recommended by the World Health Organization (WHO) as the first-line treatment for uncomplicated P. falciparum malaria.
However, while the widespread use of artemisinin-based regimens has markedly reduced the burden of disease in malaria-endemic countries, there is increasing concern regarding the current emergence of artemisinin resistance in parts of Asia, where this will likely become an increasingly serious problem.
“Artemisinin is considered as being the last line of defense against malaria,” said study corresponding author Qingsong Lin, an assistant professor in the Department of Biological Sciences at NUS. “It would be a serious problem and disaster if the [malarial] parasites developed strong drug resistance.”
According to the WHO, as of February 2015 artemisinin resistance had been confirmed in Cambodia, Laos, Myanmar, Thailand and Vietnam. Most patients with resistant parasites still recover receiving an artemisinin-based treatment with an active partner drug.
However, along the Cambodia-Thailand border, P. falciparum has become resistant to almost all of the available antimalarial drugs, meaning that multidrug resistance could soon emerge in other parts of the region, hence the urgent need for new antimalarial treatments.
NUS researchers led by Lin and Jigang Wang, a former post-doctoral fellow in the Department of Biological Sciences and Kevin S.W. Tan, an associate professor in the Department of Microbiology and Immunology, developed chemically labeled artemisinin analogs in order to visualize the proteins targeted by artemisinin in P. falciparum, they reported in the Dec. 22, 2015, edition of Nature Communications.
The NUS research team identified 124 proteins to which the antimalarial drug, once activated, binds irreversibly. Many of these proteins are thought to be involved in essential biological processes in the malarial parasite, which would help to explain why artemisinin is such an effective antimalarial drug.
“The targeted proteins are involved in multiple essential biological processes that are required for the parasite’s survival and it is probably the collective effects of promiscuous targeting that kills the parasites,” Lin told BioWorld Asia.
“However, there could be some artemisinin targets that play more important roles in killing the parasite and by studying each individual target, we hope to discover which protein is lethal to the parasite and which could be a potential druggable anti-malaria target.”
In addition, the NUS research team was able to demonstrate for the first time that the main source of the ferrous iron necessary to activate the artemisinin was a specific iron-containing compound called heme, with this iron source previously having been controversial.
The discovery of heme being the source of the iron needed to activate artemisinin was a significant development, as it is important “to know how artemisinin works and to know the source of the activator from the parasites, which is very important for this pro-drug,” explained Lin.
Although additional artemisinin drug targets are likely to exist, these latest findings help to better understand how artemisinin kills the malaria parasite and may help lead to the development of better alternative strategies to treat malaria, given the worrisome emergence of artemisinin resistance in certain parts of the world.
“We are also studying the mechanism of the anti-cancer effects of artemisinin,” said Lin, when asked about his group’s future research plans. In addition “we are trying to develop new artemisinin analogues with better biological activity that is guided by the activation mechanism.”