The mechanism of action of the plant Chang Shan - a Chinese medicinal plant that has been used for thousands of years to treat fever caused by malaria - was revealed by scientists at the Scripps Research Institute using a device with a high separation capacity.
![(right) of the Chang Shan medicinal plant; The structural formula (in the center) of the active substance halofuginone; and the high-resolution molecular image (left) of the active site. [Courtesy of principal investigator Schimmel's laboratory].](https://www.hayadan.org.il/images/content3/2013/02/schimmel_ProRs_fig-500x353.jpg.webp)
The mechanism of action of the plant Chang Shan - a Chinese medicinal plant that has been used for thousands of years to treat fever caused by malaria - was revealed by scientists at the Scripps Research Institute using a device with a high separation capacity. The structure, published in the scientific journal Nature, shows at the atomic level how a double-headed compound derived from the active ingredient in the medicinal plant Chang Shan works.
Scientists are aware of the fact that this compound, known as halofuginone (a derivative of febrifugine), is able to suppress the immune system, but no researcher has been able to explain what is its exact mechanism of action. The long-revealed structure shows that, similar to the way a wrench works, the substance halofuginone succeeds in disrupting the activity of a molecular "machine" responsible for the process of "aminoacylation", an essential biological process that allows organisms to synthesize the proteins they need.
The medicinal plant Chang Shan, also known by its botanical name Dichroa febrifuga Lour, probably helps in the treatment of fever caused by malaria in view of the fact that a halofuginone-like substance found in the plant disrupts the same process in the parasites responsible for the disease of malaria while exterminating them in the bloodstream of a sick person. "Our new findings solve a mystery that has occupied people regarding the mechanism of action of a drug used to treat malaria for more than 2000 years," said Professor Paul Schimmel from the Scripps Research Institute.
The halofuginone substance has been tested in trials for the treatment of cancer, but the image of the molecule obtained with high resolution suggests that it has a modularity that could make it useful as a general template for the development of many drugs to treat other diseases. Aminoacylation is a critical step in the synthesis of proteins, which are the finished products of gene expression. When the genes are expressed, their DNA sequence is read and copied into an RNA sequence, which is a molecule similar to DNA. In the next step, the RNA sequence is "translated" into proteins, which are chemically very different from the DNA/RNA molecules, and which consist of chains of amino acids joined together in the order determined by the DNA/RNA sequence.
This translation process requires a collection of additional molecules called transfer RNAs (tRNAs) that move the amino acids towards the growing protein chain, where they combine like making a string of pearls. However, before they are able to place the "pearls" in the desired site, they must grasp them. Aminoacylation is the biological process by which the amino acids are attached to the transfer RNA molecule. A family of enzymes called aminoacyl-tRNA synthases is responsible for connecting the amino acids to transfer RNA and the team scientists have been studying the molecular details of this process for many years.
Their work has provided other scientists with important insights into a variety of topics, from initial development to possible targets for future drug development. The research findings show that the halofuginone substance disrupts the activity of the aminoacyl-tRNA synthase enzyme that connects the amino acid proline to its corresponding messenger RNA. It does this by blocking the active site of the enzyme, the site where the transfer RNA molecule and the amino acid meet, with each half of the molecule blocking a different side at this meeting point. Surprisingly, the lead researcher points out, the ATP molecule (the source of energy) is also needed in order for the substance halofuginone to bind to this point. Such a mechanism has never been observed in biochemistry studies. "This is a wonderful example of a situation where the substrate of the enzyme (ATP) captures the inhibitor of that enzyme, obtaining an enzyme-substrate-inhibitor coupling," adds the lead researcher.
