Scientists have been looking for an effective drug against the Hepatitis E virus (HEV), which causes liver infection with symptoms of fatigue, jaundice, stomach pain, nausea, and poor appetite. A team of researchers investigated the antiviral properties of the so-called rocaglates, which are plant compounds that inhibit viral replication.
They examined several chemically modified rocaglates for their antiviral effect. They found one group of active ingredients called the amidino group that is effective in stopping the Hepatitis E virus from replicating.
Rocaglates as Antiviral
Rocaglates inhibit the synthesis of viral proteins for different RNA viruses using their broad spectrum of antiviral compounds that has a promising safety profile. But aside from the natural rocaglates, synthetic or chemically modified rocaglates have also been developed in the past years.
According to a 2020 paper from Cell Reports, rocaglates are a diverse family of biologically active molecules that have caught the attention of scientists in the past years because of their promising activities in preclinical cancer studies.
They were initially known to inhibit the proliferation of some cancer cells before scientists found their antiviral effect against RNA viruses, including Ebola, HEV, Zika, and even SARS-CoV-2.
Chemically Modified Rocaglates Have Stronger Antiviral Effects
In the new study, led by Professor John Porco Jr., he and his team created a library of recoglates with different chemical modifications. According to Science Daily, they tested a total of 205 substances to see their effectiveness against HEV in cell culture using cancer cell lines and HEV genomes tagged with a reporter gene.
They precisely measured how successfully the virus replicates in various substances by looking at the amount of protein produced, which is located in the reporter gene. The team used half-maximum inhibitory concentration to show how strongly a substance inhibits replication of the HEV.
The lower the replication, the better the substance works. Mara Klöhn reported that the half-maximum inhibitory concentration of three of the library of rocaglates they tested is between 0.5 and 3 nanomolar compared to the natural rocaglamide silvestrol, which is three to seven nanomolar.
Since they also have cancer cell-damaging effects, the team also looked at their toxicity in healthy porcine liver cells. They found that the toxicity was lower than in the cell culture that is based on cancer cell lines.
But further studies are needed to examine the efficacy and toxicity of those successful substances. For instance, they could chemically optimize the best amidino rocaglates to see if they have a stronger effect against viral replication.
They discuss their findings in full in the study titled "Identification of Structurally Re-Engineered Rocaglates as Inhibitors Against Hepatitis E Virus Replication," published in the journal Antiviral Research.
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