"Starving" malaria parasites may help develop new antimalarial drugs

August 28th, Yan Ning, a former professor at Tsinghua University's School of Life Sciences, and Yan Wei, a professor at Tsinghua University's School of Pharmacy, published a research paper online in Cell entitled "Structural Foundations for Suppressing Plasmodium falciparum Sugar Intake". At the same time, the study's "sister article" "Targeted PfHT1 protein positive structure - other two-bit site of the development of selective antimalarial drugs" is also published online on bioprinting site BioRxiv.The
study demonstrated the different composition structures of plasmodium falciparum's key protein for energy intake, the hetose transport protein PfHT1, in combination with natural substrate glucose and an inhibitor with weak inhibitor C3361, on the basis of which the team developed a series of selective inhibitors with higher affinity, laying the foundation for the further development of the series of antimalarial drugs.malaria is an infectious disease transmitted by malaria parasites through female mosquitoes, and is a prominent problem in public health in the world today. Of the five malaria parasites that can be sent to humans, Plasmodium falciparum can infect red blood cells at various stages, causing severe systemic symptoms and even death, the greatest threat to human health.
the 1970s, Tuan and others successfully extracted artemisinin compounds with good antimalarial effects from jaundial artemisinin. To date, artemisinin-based drug combination therapy (ACT) remains the first-line treatment for malignant and severe malaria, making a prominent contribution to the global fight against malaria, and has won the 2015 Nobel Prize in Physiology and Medicine.
however, due to the emergence of drug-resistant malaria parasites, ACT therapy has seen cases of treatment failure in Southeast Asia and Africa, and the development of new antimalarial drugs has become an important scientific and public health problem that needs to be addressed urgently.The key protein for Plasmodium falciparum's intake of energy substances is the heterosaccharide transporter protein PfHT1, which has not made a breakthrough in the development of inhibitors due to the lack of structural information on the protein in early studies using PfHT1 as an antimalarial target.
"Since I began my independent research in Tsinghua in 2007, I have been engaged in structural biology and biochemistry of glycolytic proteins, working to uncover the workings of these tiny protein machines. Yanning said.
and her team analyzed the high-resolution crystal structures of the human glucose transport proteins GLUT1 and GLUT3 in 2014 and 2015.
" study of PfHT1 began many years ago, but little progress has been made due to the lack of experience in the early purification of the expression of epidural proteins. At that time, we had just accumulated a lot of lessons in the process of GLUT1 and GLUT3, Jiang Xin and Yuan Yafei took over the PfHT1 project, and soon acquired its compound structure with glucose. Yan Ning, co-author of the paper, told China Science Daily.
glucose is the main energy substance in most animal cells and can be used as a potential treatment strategy for some related diseases by inhibiting the "hunger therapy" of cell glucose intake.
"We thought, can malaria be treated with a 'starving malaria parasite'?" For Plasmodium falciparum, as long as the hetose transport protein PfHT1 this road blocked, it has no source of energy, it will not survive. Jiang Xin, ph.D., of Tsinghua University's School of Life Sciences and co-lead author of the study, said.
says the difficulty of doing so is how to directly suppress the sugar intake of the malaria parasite without affecting human cells."In drug discovery, the most traditional method is to screen to determine the seed compound, but the results of our initial screening are not ideal. Higher activity, less selective, and higher selectivity, low activity. Huang Jian, co-lead author of the study and a doctoral student in the Department of Chemistry at Tsinghua University, said. Therefore, they plan to design and develop inhibitors from the beginning.
previous studies have found that the compositional dynamics of glyco-transport proteins vary significantly, with GLUT1 opening about 1,200 times per second, and it is difficult to fix them to a single image through chemical intervention.
"If sugar transport protein is compared to keyholes, inhibitors are likened to keys, the shape of keyholes is constantly changing, making it difficult to design the corresponding keys." But if the keyhole can be secured, the design key will be easier. Huang Jian said.
Therefore, after analyzing the crystal structure of PfHT1 binding to natural substrate glucose, Jiang Xin and others chose the inhibitor C3361 as the probe molecule and analyzed the crystal structure of PfHT1 binding to it by using lipid cubic phase method.
"We found that when PfHT1 is combined with glucose, it creates a cavity. When PfHT1 is combined with C3361, the structure of PfHT1 changes dramatically, and the trans-membrane spiral TM1e and TM7b are straightened by bends, resulting in another completely new cavity in which the tail of C3361 is combined, partially blocking PfHT1's glucose intake. Yuan Yafei, co-lead author of the study and a postdoctoral student at Tsinghua University's School of Life Sciences, said.
"If the C3361, the tail binding point, is modified so that it occupies the cavity tightly and tightly, and the channel is blocked to the maximum extent possible, the PfHT1 protein can be better suppressed." He said.
, "This change in composition is completely unexpected and even upends our most basic understanding of the working mechanisms of the glyco-transshipment protein family over the past decade or so, " says Yanning, a member of the National People's Bank of China.Over the next two years, the researchers synthesized more than 100 molecules designed according to the structure and measured their activity, and found that the HTI-1 molecules inhibited better, on the basis of which they designed a better active TH-PF series of molecules, both able to combine two cavities at the same time and inhibit sugar intake.
after the malaria parasite inhibition experiments, it was found that its lethality to the malaria parasite increased, but there was no significant change in cytotoxicity.
", the TH-PF family of molecules is able to direct the suppression of sugar intake of malaria parasites, but basically does not affect the intake of glucose by other cells in the body. Huang Jian said.
a second preprinted paper, the researchers elaborated on the design ideas, configuration relationships and experimental results of a new generation of small molecule inhibitors.
" in drug design, we have developed a strategy of simultaneous inhibition of both positive structure (the cavity produced by PfHT1 plus glucose) and other structures (a derived cavity after the combination of PfHT1 and C3361). This provides a new way of thinking for the current emergence of drug-resistant malaria treatment and lays the foundation for the future development of alternative and upgraded products of artemisinin. The study's co-author, Yan Wei, told China Science Daily.
" said Yan Ning, "I have always stressed the importance of basic research, when basic research has made a breakthrough, transformation is a process of water-to-water." This time it's all about basic research, and it's possible to apply it because of unexpected discoveries. If I can develop a new antimalarial drug for clinical use on this basis in the future, then my research career will be complete. Ra
o Zi, a member of the Chinese Academy of Sciences and a professor at Tsinghua University, commented, "The new generation of compounds developed by the research team to block the energy intake of malaria parasites as a new tool is expected to address the growing problem of malaria resistance." At the same time, inhibitor design ideas are very creative, providing reference for other rational drug design. (Source: Liu Runan, China Science Journal)
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