Dichroa febrifuga, a medicinal herb that has been historically used to treat fever, is named for its active ingredient, febrifugine. |
Malaria continues to be a devastating disease, killing up to 1 million people each year, most of whom are children under the age of five in sub-Saharan Africa. There is an urgent need for new treatments since the parasite has developed resistance to most of our anti-malaria drugs.
While
effective against malaria, febrifugine is not tolerated well. What is needed is
a better understanding of how febrifugine works: how does it kill the malaria parasite? If the
natural product’s mechanism of action against malaria could be identified, it
would pave the way for the development of refined derivatives that are more
specific against the parasite and less detrimental to patients. Alas, this is
not an easy task. Over 2000 years in the making, scientists have now identified
an enzyme in the parasite that is inhibited by febrifugine. That enzyme is
called prolyl-tRNA synthetase.
Prolyl-tRNA synthetase is critical for the production of proteins in a cell, a process known as translation. As shown in the figure below, messenger RNA (mRNA), which serves as the “middle man” conveying the information in genes to build proteins, is read by molecular machines called ribosomes. Another type of RNA molecule called transfer RNA (tRNA) recognizes specific nucleotide sequences in the mRNA, bringing the corresponding amino acid to the ribosome so it can be added to a growing protein sequence.
Prolyl-tRNA synthetase is critical for the production of proteins in a cell, a process known as translation. As shown in the figure below, messenger RNA (mRNA), which serves as the “middle man” conveying the information in genes to build proteins, is read by molecular machines called ribosomes. Another type of RNA molecule called transfer RNA (tRNA) recognizes specific nucleotide sequences in the mRNA, bringing the corresponding amino acid to the ribosome so it can be added to a growing protein sequence.
Aminoacyl-tRNA
synthetase enzymes are needed to “charge” the tRNA; in other words, they attach
the correct amino acid to the correct tRNA. When prolyl-tRNA synthetase is
blocked by febrifugine, the amino acid proline does not get attached to tRNA.
This leads to a buildup of “uncharged” tRNA, which is interpreted as a sign of
starvation by the cell (or by the single-celled malaria parasite in this case).
Proline is a common amino acid needed to build many proteins, and when prolyl-tRNA
synthetase isn’t able to do its job, protein production grinds to a halt.
Even
better, this enzyme is required in multiple stages of the parasite’s life
cycle, knocking out both the liver and the blood forms. But as mentioned above,
humans do not tolerate febrifugine very well, probably because we also have a version of prolyl-tRNA synthetase and perhaps other proteins
that febrifugine poisons. Having identified this drug target is helping
researchers develop derivatives of febrifugine, such as halofuginol, that act
more strongly against the parasite’s prolyl-tRNA synthetase with less toxicity
in humans.
Halofuginol is chemically similar to febrifugine (see above), having potent activity against malaria but less adverse effects on the host. |
Parasites
that were able to grow better in febrifugine had their genomes sequenced. Such
a feat would have taken years and millions of dollars not long ago, but today
it has become routine. The genome sequence of the febrifugine-resistant
parasites contained a common mutation in the gene encoding prolyl-tRNA
synthetase, which signaled that this enzyme plays a critical role in the drug’s
action. Understanding how the parasite develops resistance also helps
scientists design compounds that act on the target differently. As you may
surmise, we are in a constant “arms race” with these insidious microbes, but this discovery is a step towards a victory for us.
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Herman JD, Pepper LR, Cortese JF, Estiu G, Galinsky K, Zuzarte-Luis V, Derbyshire ER, Ribacke U, Lukens AK, Santos SA, Patel V, Clish CB, Sullivan WJ Jr, Zhou H, Bopp SE, Schimmel P, Lindquist S, Clardy J, Mota MM, Keller TL, Whitman M, Wiest O, Wirth DF, & Mazitschek R (2015). The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs. Science translational medicine, 7 (288) PMID: 25995223
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