Viruses
use the molecular repertoire of the host cell to replicate. Researchers
want to exploit this for the treatment of influenza. The team has
identified a compound that inhibits the body's own methyltransferase
MTr1, thereby limiting the replication of influenza viruses. The
compound proved effective in lung tissue preparations and mouse studies
and showed synergistic effects with already approved influenza drugs.
The study is now published in the journal Science.
To
replicate, viruses need a host cell. There they introduce their genetic
information in the form of the nucleic acids DNA or RNA. These
molecular blueprints are used in the host cell to produce new viruses.
In order to distinguish foreign from its own nucleic acids, the cell
uses a kind of labeling system. Own RNA, for example, is tagged with a
molecular cap that identifies it as non-hazardous. This enables the
immune system to react specifically to threats.
The
molecular cap is a methylated nucleoside: A small molecule attached to
the end of the RNA chain. Tagged in this way, the RNA does not trigger
an immune response. However, if there is RNA in the cell that lacks the
cap structure, it is recognized by the immune receptor RIG-I, and the
immune system is alerted. To escape this, influenza viruses have
developed a special mechanism. They steal the molecular cap from
cellular RNA molecules and transfer it to their own RNA. This process is
called cap-snatching.
The
enzyme MTr1 provides cellular mRNA with a cap structure and thus
functions as the cell's "nucleic acid labeler". The team has now been
able to show how much influenza viruses depend on the function of the
enzyme MTr1. "While other viruses, such as SARS-CoV-2, are able to cap
their RNA molecules on their own, influenza viruses rely on stealing
existing caps," says the lead author of the paper. "If the function of
MTr1 is disrupted in the cell, there are no caps available to transfer
to viral RNA." The activity of MTr1 is thus essential for the
replication of the influenza virus in the cell.
The
researchers want to harness this dependence for the treatment of
influenza infections. To this end, they searched for inhibitors that
specifically inhibit MTr1. The team investigated how the substances in
the infected tissue affect the amount of virus particles produced. The
researchers tested this both in mouse models and in human lung tissue
preparations. These so-called lung explants come from patients who have
undergone lung surgery. "Among thousands of candidates, we were able to
identify a molecule that inhibits MTr1 in human lung explants and also
in vivo in mice, curtailing influenza replication," reports the senior
author.
The
inhibitor is a derivative of a natural product called trifluoromethyl
tubercidin (TFMT), which is produced by bacteria of the genus
Streptomyces. "We hope this study will lead to the development of new
treatments for influenza," says the author. In the present study, the
researchers were already able to demonstrate that TFMT works together
with approved drugs against influenza infections. It was even possible
to show a clear synergistic effect with regard to the number of virus
particles produced in the tissue.
https://www.science.org/doi/10.1126/science.add0875