Molecular picture of how antiviral drug molnupiravir works

A cryo-EM structure showing how the antiviral drug molnupiravir drug Read more

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antiviral drugs

Molecular picture of how antiviral drug molnupiravir works

Scientists at the Max Planck Institute for Biophysical Chemistry in Germany have generated a structure showing how the antiviral drug molnupiravir drug works.

Molnupiravir was originally discovered by Emory’s non-profit drug development company DRIVE, and is now being developed by Merck. The drug, previously known as EIDD-2801, can be provided as a pill in an outpatient setting – potentially a step up in ease of distribution and convenience.

Molnupiravir is currently in clinical trials for non-hospitalized people with COVID-19 and at least one risk factor; results are expected later in the fall of 2021. Merck also recently began a prevention study for adults who live with a currently infected person. Previous small-scale studies conducted by Merck’s partner Ridgeback Biotherapeutics showed that the drug is safe and can reduce viral levels to undetectable in non-hospitalized people within five days.

The structure shows how the active form of molnupiravir interacts with the enzyme that makes new copies of the SARS-CoV-2 genome (RNA-dependent RNA polymerase). Incorporation of the active form of the drug into the RNA genome leads to mutations – so many that the virus can’t generate enough accurate copies of itself. Molnupiravir is likely to work in a similar way when deployed against other viruses such as influenza.

The cryo EM (cryo-electron microscopy) structure comes from Patrick Cramer’s group in Göttingen, along with chemists at the University of Würzburg, and was published in Nature Structural & Molecular Biology. Last year, Cramer’s group also generated a structure of the replicating viral RNA polymerase. The video below comes courtesy of the Max Planck Institute and Cramer’s lab.

The animation shows how the RNA-like building blocks of molnupiravir (M, yellow) form atypical pairings with adenine (A) and guanine (G) in the viral RNA. This leads to mutations in the viral RNA, interfering with efficient replication of SARS-CoV-2.
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Repurposing a rheumatoid arthritis drug for COVID-19

For COVID-19, many researchers around the world have tried to repurpose drugs for other indications, often unsuccessfully. New clinical trial results show that baricitinib, developed by Eli Lilly and approved for rheumatoid arthritis, can speed recovery and may reduce mortality in some groups of hospitalized COVID-19 patients.

How did this study, sponsored by the National Institute of Allergy and Infectious Diseases, come together? In part, through decade-long groundwork laid by investigators at Emory, and their collaborations with others.

The ACTT-2 results were recently published in New England Journal of Medicine. (More formal NIAID and Emory press releases are here and here.)

For several years, drug hunter and virologist Raymond Schinazi and his team had been investigating a class of medications called JAK inhibitors, as an option for tamping down chronic inflammation in HIV infection. Schinazi was one of the first at Emory to investigate the use of anti-inflammatory agents for herpesviruses and HIV in combination with antiviral drugs. He believed that these viruses “hit and run,” leaving behind inflammation, even if they later go into hiding and seem to disappear.

In Schinazi’s lab, Christina Gavegnano had shown that JAK inhibitors had both anti-inflammatory and antiviral properties in the context of HIV — a project she started as a graduate student in 2010. JAK refers to Janus kinases, which regulate inflammatory signals in immune cells.

 “Our team was working on this for 10 years for HIV,” Gavegnano says. “There was a huge amount of data that we garnered, showing how this drug class works on chronic inflammation and why.” 

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Posted on by Quinn Eastman in Immunology Leave a comment

Antios moving ahead with potential drug vs hepatitis B

Antios Therapeutics is moving ahead with Phase I clinical studies in Canada and Europe of an antiviral drug aimed at hepatitis B. Antios was formed in 2018 based on technology licensed from DRIVE, the non-profit drug development company owned by Emory.

Antios is developing ATI-2173, which was designed to direct a form of the drug clevudine to the liver. Pharmasset, formed by Emory scientists and later acquired by Gilead, was previously developing clevudine against hepatitis B. Pharmasset decided to stop clinical studies of clevudine in 2009 because of reports of drug-induced myopathy from South Korea. ATI-2173 is supposed to selectively deliver the drug to the liver, potentially eliminating off-target effects.

(DRIVE is also developing an drug with activity against influenza and the new coronavirus, but hepatitis B – with a weird partly double-stranded DNA genome— is quite different from both flu and coronaviruses. It does underline DRIVE’s experience with antivirals.)

Antios recently announced that the US Patent and Trademark Office has issued a notice of allowance for a patent covering ATI-2173. A full description is available from the World Intellectual Property Organization portal.

The patent is based on research carried out at Emory by Antios CEO and co-founder Abel De La Rosa, PhD, who was previously chief scientific officer at DRIVE and Emory Institute for Drug Development, and before that, an executive at Pharmasset. Read more

Posted on by Quinn Eastman in Immunology Leave a comment

What are rods and rings?

This image of mouse embryonic fibroblasts comes from Cara Schiavon, a graduate student in Rick Kahn’s lab in the Department of Biochemistry. It was impressive enough to capture interest from Emory Medicine‘s graphics designer Peta Westmaas. The light green shapes are “Rods and Rings,” structures that were identified just a few years ago by scientists studying how cells respond to antiviral drugs, such as those used against hepatitis C.

The rod and ring structures appear to contain enzymes that cells use for synthesizing DNA building blocks. Patients treated with some antiviral drugs develop antibodies against these enzymes.

The turquoise color represents microtubules, components of cells’ internal skeletons. The orange color shows DNA within nuclei. The spots in the nuclei are areas where DNA is more compact. The overall image is a “z-stack projection” acquired using the Olympus FV1000 confocal microscope in Emory’s Integrated Cellular Imaging Core.

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