Washington: Chinese herbalists have been using a root extract, commonly known as Chang Shan, from a type of hydrangea that grows in Tibet and Nepal, to treat Malaria for roughly two thousand years.
Experts in more recent studies have suggested that halofuginone, a compound derived from this extract’s bioactive ingredient, could be used to treat many autoimmune disorders as well.
Now, researchers from the Harvard School of Dental Medicine have discovered the molecular secrets behind this herbal extract’s power.
It turns out that halofuginone (HF) triggers a stress-response pathway that blocks the development of a harmful class of immune cells, called Th17 cells, which have been implicated in many autoimmune disorders.
“HF prevents the autoimmune response without dampening immunity altogether. This compound could inspire novel therapeutic approaches to a variety of autoimmune disorders,” said Malcolm Whitman, a professor of developmental biology at Harvard School of Dental Medicine and senior author on the new study.
Tracy Keller, an instructor in Whitman’s lab and the first author on the study added, “This study is an exciting example of how solving the molecular mechanism of traditional herbal medicine can lead both to new insights into physiological regulation and to novel approaches to the treatment of disease,”
This study involved an interdisciplinary team of researchers at Massachusetts General Hospital and elsewhere.
For the current study, the researchers investigated how HF activates the amino acid response pathway, or AAR, looking at the most basic process that cells use to translate a gene’s DNA code into the amino acid chain that makes up a protein.
The researchers were able to home in on a single amino acid, called proline, and discovered that HF targeted and inhibited a particular enzyme (tRNA synthetase EPRS) responsible for incorporating proline into proteins that normally contain it. When this occurred, the AAR response kicked in and produced the therapeutic effects of HF-treatment.
Providing supplemental proline reversed the effects of HF on Th17 cell differentiation, while adding back other amino acids did not, establishing the specificity of HF for proline incorporation.
Added proline also reversed other therapeutic effects of HF, inhibiting its effectiveness against the malaria parasite as well as certain cellular processes linked to tissue scarring. Again, supplementation with other amino acids had no such effect. Such mounting evidence clearly demonstrated that HF acts specifically to restrict proline.
The researchers think that HF treatment mimics cellular proline deprivation, which activates the AAR response and subsequently impacts immune regulation. Researchers do not yet fully understand the role that amino acid limitation plays in disease response or why restricting proline inhibits Th17 cell production.
Nevertheless, “AAR pathway is clearly an interesting drug target, and halofuginone, in addition to its potential therapeutic uses, is a powerful tool for studying the AAR pathway,” said Whitman.
This study has been published in Nature Chemical Biology.