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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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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Social isolation and the adolescent brain

We can’t read Emory neuroscientist Shannon Gourley’s papers on social isolation in adolescent mice, without thinking about how the COVID-19 pandemic is affecting children and teenagers. Much of the experimental work was completed before the pandemic began. Still, in the future, researchers will be studying the effects of the pandemic on children, in terms of depression and anxiety, or effects on relationships and education. They could look to neuroscience studies such as Gourley’s for insights into brain mechanisms.

What will the social isolation of the pandemic mean for developing brains?

In the brain, social isolation interferes with the pruning of dendritic spines, the structures that underly connections between neurons. One might think that more dendritic spines are good, but the brain is like a sculpture taking shape – the spines represent processes that are refined as humans and animals mature.

Mice with a history of social isolation have higher spine densities in regions of the brain relevant to decision-making, such as the prefrontal cortex, the Emory researchers found.

In a recently published review, Gourley and her co-authors, former graduate student Elizabeth Hinton and current MD/PhD Dan Li, say that more research is needed on whether non-social enrichment, such as frequent introduction of new toys, can compensate for or attenuate the effects of social isolation.

This research is part of an effort to view adolescent mental health problems, such as depression, obesity or substance abuse, through the prism of decision-making. The experiments distinguish between goal-oriented behaviors and habits. For humans, this might suggest choices about work/school, food, or maybe personal hygiene. But in a mouse context, this consists of having them poke their noses in places that will get them tasty food pellets, while they decode the information they have been given about what to expect. 

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COVID-triggered autoimmunity may be mostly temporary

In people with severe COVID-19, the immune system goes temporarily berserk and generates a wide variety of autoantibodies: proteins that are tools for defense, but turned against the body’s own tissues.

During acute infection, COVID-19 patients’ immune systems resemble those of people with diseases such as lupus or rheumatoid arthritis. However, after the storm passes, the autoantibodies decay and are mostly removed from the body over time, according to a study of a small number of patients who were hospitalized and then recovered. 

In a preprint posted on medRxiv, Emory immunologists provide a view of the spectrum of what COVID-generated autoantibodies react against, both during acute infection and later. Note: the results have not yet been published in a peer-reviewed journal.

The findings on COVID-19-triggered autoimmunity may have implications for both the treatment of acute infection and for long-haulers, in whom autoantibodies are suspected of contributing to persistent symptoms such as fatigue, skin rashes and joint pain.

During acute infection, testing for autoantibodies may enable identification of some patients who need early intervention to head off problems later. In addition, attenuation of autoantibody activity by giving intravenous immunoglobulin (IVIG) – an approach that has been tested on a small scale — may help resolve persistent symptoms, the Emory investigators suggest.

Researchers led by Ignacio Sanz, MD and Frances Eun-Hyung Lee, MD, isolated thousands of antibody-secreting cells from 7 COVID-19 patients who were in ICUs at Emory hospitals. They also looked for markers of autoimmunity in a larger group of 52 COVID-19 ICU patients.

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Detecting vulnerable plaque with a laser-induced whisper

A relatively new imaging technique called photoacoustic imaging or PAI detects sounds produced when laser light interacts with human tissues. Working with colleagues at Michigan State, Emory immunologist Eliver Ghosn’s lab is taking the technique to the next step to visualize immune cells within atherosclerotic plaques.

The goal is to more accurately spot vulnerable plaque, or the problem areas lurking within arteries that lead to clots, and in turn heart attacks and strokes. A description of the technology was recently published in Advanced Functional Materials

“I believe we are now closer to developing a more precise method to diagnose and treat life-threatening atherosclerotic plaques,” Ghosn says. “Our method could be deployed in combination with IVUS to significantly improve its accuracy and sensitivity, or it could be used non-invasively.”

From science fiction movies, we might think lasers come with a “pow” sound. Photoacoustic imaging is more like listening for a whisper: sounds associated with heat generated by a laser pulse when it is absorbed by tissue.

Earlier this year, the FDA approved a photoacoustic imaging system for detection of breast cancer. Several companies are developing photoacoustic imaging systems, and what we might call “plain vanilla” PAI is currently being tested on carotid artery plaque in clinical studies in Europe.

Ghosn’s approach, developed with biomedical engineer Bryan Smith at Michigan State, adds specificity by adding nanoparticle probes taken up by macrophages, the immune cells that accumulate within atherosclerotic plaques. The nanoparticles, administered before imaging, act as contrast agents.

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Neutrophils flood lungs in severe COVID-19

“First responder” cells called neutrophils are the dominant type of immune cells flooding the airways of people with severe COVID-19, according to a recent analysis of African-American patients in Emory hospitals.

The findings were posted on the preprint server Biorxiv prior to peer review.

Neutrophils are the most abundant immune cells in the blood, and usually the first to arrive at the site of a bacterial or viral infection. But in the lungs of severe COVID-19 patients, neutrophils camp out and release tissue-damaging enzymes, the new research shows. They also produce inflammatory messengers that induce more neutrophils to come to the lungs. 

Lung inflammation photo from NIEHS. Most of these dense small cells are neutrophils

This circulating cell type enters the lung and initiates a self-sustaining hyper-inflammation that leads to acute respiratory distress syndrome (ARDS), the leading cause of mortality in COVID-19, says lead author Eliver Ghosn assistant professor of medicine at Emory University School of Medicine.

“Our findings reveal novel therapeutic targets, and developing tactics to intervene could benefit severe patients in the ICU, particularly those that are most vulnerable,” Ghosn says. “We compared our lung data with matching blood samples for all the patients, and we were able to identify the subtype of neutrophils in the blood that is most likely to infiltrate the lungs of severe patients and cause ARDS.”

Somewhat counter-intuitively, Emory researchers had difficulty detecting SARS-CoV-2 infected cells in the upper airways of hospitalized patients. This result, consistent with findings by others, may explain why antiviral drugs such as remdesivir are ineffective once systemic inflammation has gained momentum; lung injury comes more from the influx of immune cells, such as neutrophils, rather than viral infection itself.

When Ghosn and his colleagues began examining immune cells in COVID-19, they found that almost all of the hospitalized patients they encountered were African-American. This highlights the racial disparities of the COVID-19 pandemic, especially in Georgia, and Ghosn’s team decided to “lean in” and focus on African-Americans. They collaborated closely with Eun-Hyung Lee’s lab at Emory to collect samples from hospitalized patients. 

“We believe these results can have broader implications and be applied to other demographics that suffer from similar lung pathology,” Ghosn says.

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Brain organoid model shows molecular signs of Alzheimer’s before birth

In a model of human fetal brain development, Emory researchers can see perturbations of epigenetic markers in cells derived from people with familial early-onset Alzheimer’s disease, which takes decades to appear. This suggests that in people who inherit mutations linked to early-onset Alzheimer’s, it would be possible to detect molecular changes in their brains before birth.

The results were published in the journal Cell Reports.

“The beauty of using organoids is that they allow us to trace back what could happen at the molecular level in early developmental stages,” says lead author Bing Yao, PhD, assistant professor of human genetics at Emory University School of Medicine. “A lot of epigenetic studies on Alzheimer’s use postmortem brains, which only represent the end point of the disease, in terms of molecular signatures.”

Photos of brain organoid cultures courtesy of Zhexing Wen

The brain organoid model allows scientists to probe human fetal brain development without poking into any babies; they have also been used to study schizophrenia, fragile X syndrome and susceptibility to Zika virus.

Co-author Zhexing Wen helped develop the model, in which human pluripotent stem cells recapitulate early stages of brain development, corresponding to 17-20 weeks after conception. The stem cell lines were obtained from both healthy donors and from people with mutations in PSEN1 or APP genes, which lead to early-onset Alzheimer’s.

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“Trojan horse” antibiotic underperforms; does heteroresistance explain?

A stealthy form of antibiotic resistance may be limiting the effectiveness of a new weapon against bacterial infections, research from Emory’s Antibiotic Resistance Center suggests.

The antibiotic cefiderocol (Fetroja) was developed by the Japanese company Shionogi, and was FDA-approved for the treatment of complicated urinary tract infections in 2019 and for hospital-acquired bacterial pneumonia in 2020.

In a recent international clinical trial testing cefiderocol in patients with serious infections resistant to carbapenems (CREDIBLE-CR), outcomes weren’t significantly better for cefiderocol, compared to patients who received the best available therapy otherwise. In addition, mortality was actually higher for patients treated with cefiderocol.

Resistance to carbapenems, a common class of antibiotics, is a major problem and precisely what cefiderocol was meant to circumvent. These results have had infectious disease experts asking why cefiderocol didn’t perform better, and wondering what place it should take in physicians’ tool boxes.

Cefiderocol has been touted as a “Trojan horse” antibiotic

Emory scientists think that cefiderocol’s effectiveness may have been undermined by heteroresistance, in which a small subpopulation of bacteria is already resistant to a given antibiotic before it is applied. Heteroresistance is often missed by standard tests.

Researchers led by David Weiss, director of Emory’s Antibiotic Resistance Center, surveyed bacterial samples from the Georgia Emerging Infections program, reporting their findings in Lancet Infectious Diseases.

Postdoc Jacob Choby and senior research specialist Tugba Ozturk were the primary surveyors.

They discovered that heteroresistance to cefiderocol was widespread in samples from Georgia, ranging from 9 to 59 percent, depending on the type of bacteria. Weiss acknowledges that he and his colleagues are making indirect inferences about the bacterial infections from the CREDIBLE-CR trial; they would like to test such strains directly in the future.

Still, the prevalence of cefiderocol heteroresistance is similar between bacteria isolated from different countries. Also, the prevalence among various kinds of bacteria in Georgia roughly matches up with mortality rates in the CREDIBLE-CR trial – particularly among the kinds that were the most troublesome (Acinetobacter).

“We’ve shown that heteroresistance can cause treatment failure in animal models, but these data suggest that it may be contributing to treatment failure in hospitals right now,” Weiss says.

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Revealing brain temperature via MR imaging and biophysical modeling

Magnetic resonance (MR) imaging technology and biophysical modeling being developed at Emory and Georgia Tech could provide more accurate predictions of brain temperature, which is difficult for doctors to directly assess. The temperature of the brain is critical information after someone has experienced a stroke or cardiac arrest, and even more important during treatment. 

The results of a pilot study were published today in the journal Communications Physics.

The project grew out of a collaboration between Candace Fleischer, PhD, an assistant professor of radiology and imaging sciences at Emory, and Andrei Fedorov, PhD, a world expert on thermodynamics and biophysical modeling and a professor of mechanical engineering at Georgia Tech. The first author of the paper is Georgia Tech/Emory biomedical engineering graduate student Dongsuk Sung.

The researchers developed a biophysical model based on heat transfer, using data acquired by imaging individuals’ brain tissue and blood vessel structure. As predicted and in agreement with MR whole brain measurements, brain temperature is slightly higher than core body temperature – about 1 degree C; there are “hot” spots in the brain domains with high rate of metabolism; and the regions of the brain that are closer to the scalp are also slightly cooler than the midbrain.

“We find that every subject’s brain temperature and spatial temperature patterns are different, setting the stage for a personalized approach to managing brain temperature,” says Fleischer, who is also a faculty member in the Wallace H. Coulter Department of Biomedical Engineering and Georgia Tech at Emory.

Metabolic heat, cerebral blood flow, and model-predicted brain temperature maps for three healthy volunteers. From Sung et al (2021), via Creative Commons 4.0

Researchers then compared the predictions of their model with measurements based on the magnetic resonance properties of water, which change with temperature, and the temperature-insensitive brain metabolite N-acetylaspartate. The Communications Physics paper shows temperature modeling and MR-based measurements for three healthy volunteers.

Fleischer recently received a three-year, $400,000 Trailblazer grant from the National Institute of Biomedical Imaging and Bioengineering to monitor brain temperature while patients are undergoing therapeutic hypothermia after cardiac arrest. More information about that here.

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Killing viruses, pointy ears or not

After success finding flu virus-killing peptides in frog slime, immunologist Joshy Jacob and his colleagues at Emory Vaccine Center turned their attention from influenza to Zika. Their follow-up paper on an antiviral peptide that destroys Zika virus was published earlier this year in Scientific Reports.

The findings illustrate how frogs’ skin secretions are a rich source of potential antiviral weapons, even though Zika itself is not thought to infect frogs. Jacob reports his team is currently investigating peptides with activity against SARS-CoV-2. Lab Land is expecting to hear more about that soon.

But before SARS-CoV-2, you may recall Zika as a virus of public health concern. Carried by mosquitoes, its insidious infection can lead to neurological birth defects and disabilities in infants and Guillain-Barre syndrome in adults. Neither antiviral drugs or vaccines are available against Zika, leaving the field wide open for Jacob’s amphibian approach.

Jacob and his crew decided to call their antiviral Zika-destroying peptide Yodha, which means “warrior” in Sanskrit. Just in case you might have some other associations for that word, which sounds like the name of a few recent Bollywood movies, as well as a diminutive Jedi trainer from the Star Wars universe.

The Yodha peptide emerged from a screen of many frog peptides, and it was the only one of several Zika-killing peptides that was not toxic to human red blood cells. The peptide comes from the skin of Indosylvirana aurantiaca which lives in the western Ghats of India and is commonly known as the “golden frog.” (The website India Biodiversity, linked above, has photos of the frogs.)

Using electron microscopy, Jacob’s lab could show that the Yodha peptide blasts Zika virus particles apart with a few minutes of exposure. It was active against Zika and all four varieties of the related dengue virus.

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New antibiotic tactic vs gonorrhea

A new antibiotic compound can clear infection of multi-drug resistant gonorrhea in mice with a single oral dose, according to a new study led by researchers at Penn State and Emory.

Like other antibiotics, this one targets the ribosome, the factories that generate proteins in bacterial (and human) cells. But it does so at a site that is different from other antibiotics. This one interferes with the process of trans-translation, which bacteria use to rescue their ribosomes out of rough spots.

The results were published in Nature Communications. This was a collaboration involving several groups: biochemist Christine Dunham’s at Emory and Ken Keiler’s at Penn State, along with others at Florida State, the Uniformed Services University and the Massachusetts-based pharmaceutical company Microbiotix.

Zachary Aron, director of chemistry at Microbiotix, is the first author of the paper, and the compound is called MBX-4132. It is also active against other Gram-positive bacteria, including tuberculosis and Staph aureus, and the company says it will continue to optimize it.

At Emory, Dunham’s lab used cryo-electron microscopy to produce high-resolution images of the compound as it binds to the bacterial ribosome — see below.

Christine Dunham’s lab specializes in ribosomal structural studies

“A derivative of MBX-4132 binds to a location on the ribosome that is different from all known antibiotic binding sites,” Dunham says. “The new drug also displaces a region of a ribosomal protein that we think could be important during the normal process of trans-translation. Because trans-translation only occurs in bacteria and not in humans, we hope that the likelihood of the compound affecting protein synthesis in humans is greatly reduced, a hypothesis strongly supported by the safety and selectivity studies performed by Microbiotix.”

Multi-drug resistant gonorrhea is listed by the CDC as one of the five most urgent threats, among antibiotic resistant bacteria. Half of all gonorrhea infections are resistant to at least one antibiotic.

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