Pediatrics: Researchers Discover New Drug, DMA-153 Against Enterovirus 71 That Causes Hand, Foot And Mouth Disease
Pediatrics: Researchers from Case Western Reserve University-Ohio, Duke University-North Carolina and Rutgers Robert Wood Johnson Medical School-New Jersey have discovered a new drug candidate against enterovirus 71, a common cause of hand, foot and mouth disease in infants and young children.
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The study team first screened an RNA-biased small molecule library using a peptide-displacement assay to identify ligands for the stem loop II structure of the EV71 internal ribosomal entry site, which was previously shown to impact viral translation and replication.
One ligand, DMA-135, decreased viral translation and replication in cell-based studies in a dose-dependent manner with no significant toxicity. Structural, biophysical, and biochemical characterization support an allosteric mechanism in which DMA-135 induces a conformational change in the RNA structure that stabilizes a ternary complex with the AUF1 protein that then represses translation. This mechanism was further supported by pull-down experiments in cell culture.
The research findings have been already peer-reviewed and due for publication in the journal: Nature Communications sometime next week. The initial preprint version is available here.
https://www.biorxiv.org/content/10.1101/2020.03.10.981167v1
The study team identified the compound of interest that is a small molecule that binds to RNA, the virus's genetic material, and changes its 3-D shape in a way that stops the virus from multiplying without harming its human host.
To date there are no FDA-approved drugs or vaccines for enterovirus 71, which affects hundreds of thousands of children each year, particularly in Southeast Asia.
Although most individuals get better within 7 to 10 days after suffering little more than a fever and rash, severe cases can cause brain inflammation, paralysis and even death.
The study findings could pave the way for new treatments for other viral infections as well, says the study team.
Typically most drugs are designed to bind to proteins to block or disrupt their role in causing disease. But much of the genome in humans and their microbial pathogens doesn't code for proteins, which means that only a fraction of their genetic material is targeted by existing drugs.
Co-author Dr Amanda Hargrove, associate professor of chemistry at Duke.
"For diseases that don't have good treatments, maybe the problem is we've been targeting the wrong thing."
Rather than target proteins, Dr Hargrove and others are looking for small molecules that target RNA, which most drug discovery programs have overlooked.
Typically whenever a virus like enterovirus 71 (or SARS-CoV-2, the virus that causes COVID-19) infects a human cell, it injects its RNA into the cell, hijacking the internal machinery to make copies of itself that eventually burst out to infect neighboring cells.
Past work on enterovirus 71 singled out one part of its RNA structure that helps the virus co-opt the host machinery it needs to replicate. This RNA region folds
over on itself to form a hairpin, with a bulge in the middle where unpaired nucleotides balloon out to one side.
The study team said that the only way to find an effective drug was if a drug could be developed to inhibit this region, then only it might be able to block the virus before it has a chance to spread.
Dr Hargrove and colleagues screened a library of some 30 small molecules, looking for ones that bind tightly to the bulge and not other sites in the virus's RNA.
Often the RNA is a wiggly molecule; when it binds to other molecules such as host proteins or small molecule drugs it takes on different 3-D shapes.
The study team identified one molecule, dubbed DMA-135 that enters infected human cells and attaches itself to the surface of the bulge, creating a kink in this region.
This unique shape change, in turn, opens access to another molecule ie a human repressor protein that blocks the "reading out" of the virus's genetic instructions, stopping viral growth in its tracks.
In the research, the study team was able to use the molecule to stop the virus from building up inside human cell cultures in the lab, with bigger effects at higher doses.
Dr Hargrove says it would take at least five years to move any new drug for hand, foot and mouth disease from the lab to medicine cabinets. Before their small molecule could reach patients, the next step is to make sure it's safe and effective in mice.
The researchers are also building on their success with enterovirus 71 and looking at whether RNA-targeting small molecules could be used to tackle other RNA viruses too, including SARS-CoV-2.
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