Major advance in race for SARS-CoV-2 inhibitor drugs

 

Mpro dimer from SARS-CoV-2 in complex with the inhibitory peptide (13)
 following 100 ns of molecular dynamics simulation.
Credit: University of Bristol

A new advance towards the development of drugs specifically designed to inhibit a key SARS-CoV-2 enzyme is reported in the Royal Society of Chemistry's leading journal, Chemical Science. The international team, led by scientists from the Universities of Oxford and Bristol, has designed new peptide molecules and shown that they block (inhibit) the virus’s main protease [Mpro] - a prominent SARS-CoV-2 drug target.

Once SARS-CoV-2 invades a healthy human cell, the virus's own genetic material commandeers the infected cell's machinery, forcing it to make new copies of the virus. A vital step in this viral life cycle involves cutting a very long 'polyprotein' into its constituent viral proteins. SARS-CoV-2 has two molecular machines called protease enzymes that act as 'molecular scissors'. One of these, called the main protease, or 'Mpro' for short, has the vital role of chopping up the polyprotein, cutting it at 11 different places.

In the early days of the pandemic lockdown, Professor Garrett Morris at the University of Oxford, brought together a group of scientists to try to understand Mpro, with the aim of helping develop drugs against COVID-19. Meeting weekly over many months by Zoom, this group combined their computational and experimental expertise, and grew to include scientists from several different countries. From Bristol, this included Professors Adrian Mulholland and Jim Spencer, Dr Deborah Shoemark, PhD student Becca Walters, and other colleagues. Using a wide array of computational molecular modelling techniques including interactive molecular dynamics in virtual reality, quantum mechanics, peptide design and protein-ligand interaction analysis, the scientists were able to build an atomic level picture of the structure, dynamics and interactions of Mpro.

From these models, the team were able to find how the viral Mpro 'molecular scissors' work. They then designed new peptides, which are short pieces of protein, as inhibitors, to bind tightly to Mpro and prevent it from working, stopping the virus dead in its tracks. But did they work?

All 11 protein cut sites and four of these designed peptides were synthesized and tested in the Chemistry Research Laboratory at the University of Oxford. Experiments, led by Professor Chris Schofield at Oxford, showed that the novel peptides - designed by Dr Deborah Shoemark, with software developed in Bristol - not only bound to the molecular scissors, but they outcompeted the natural protein cut sites and so inhibited Mpro.

Adrian Mulholland, Professor of Chemistry at the University of Bristol and one of the study's lead authors, said: "Despite the development of successful vaccines in record time, new antiviral drugs are desperately needed. To date there are no drugs designed specifically to target COVID-19. Computational molecular modelling can really help with this. As we’ve shown here, computational design can produce molecules that actually stop the Mpro enzyme from working."

Dr Deborah Shoemark, Senior Research Associate (Biomolecular Modelling) in the School of Biochemistry, added: "It has been great to work together on this, combining our ideas and methods to get a really detailed picture of how this viral enzyme works – and to design molecules that actually stop it from working. Understanding Mpro specificity provides the potential to exploit vulnerabilities of the SARS-CoV-2 virus that may provide routes to new antivirals."

Professor Mulholland added: "This collaboration has really shown how sharing of models, data and expertise can help get understanding and make progress much more quickly. Garrett (Morris) built a fantastic team, and it has been exciting to work together on this. It’s how science should be done – particularly in the face of pressing problems like the COVID-19 pandemic."

The study was funded through several grants including support from the EPSRC, BBSRC and the Wellcome Trust.

Source/Credit: University of Bristol

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High-speed alloy creation might revolutionize hydrogen’s future

 

Researchers from Sandia National Laboratories and international collaborators used computational approaches, including explainable machine learning models, to elucidate new high-entropy alloys with attractive hydrogen storage properties and direct laboratory synthesis and validation.

A Sandia National Laboratories team of materials scientists and computer scientists, with some international collaborators, have spent more than a year creating 12 new alloys — and modeling hundreds more — that demonstrate how machine learning can help accelerate the future of hydrogen energy by making it easier to create hydrogen infrastructure for consumers.

Vitalie Stavila, Mark Allendorf, Matthew Witman and Sapan Agarwal are part of the Sandia team that published a paper detailing its approach in conjunction with researchers from Ångström Laboratory in Sweden and Nottingham University in the United Kingdom.

“There is a rich history in hydrogen storage research and a database of thermodynamic values describing hydrogen interactions with different materials,” Witman said. “With that existing database, an assortment of machine-learning and other computational tools, and state-of-the art experimental capabilities, we assembled an international collaboration group to join forces on this effort. We demonstrated that machine learning techniques could indeed model the physics and chemistry of complex phenomena which occur when hydrogen interacts with metals.”

Having a data-driven modeling capability to predict thermodynamic properties can rapidly increase the speed of research. In fact, once constructed and trained, such machine learning models only take seconds to execute and can therefore rapidly screen new chemical spaces: in this case 600 materials that show promise for hydrogen storage and transmission.

“This was accomplished in only 18 months,” Allendorf said. “Without the machine learning it could have taken several years. That’s big when you consider that historically it takes something like 20 years to take a material from lab discovery to commercialization.”

Autistic individuals are more likely to be LGBTQ+

The findings have important implications for the healthcare and support of autistic individuals. The results are published in the journal Autism Research.  

For many years it was wrongly assumed that autistic individuals are uninterested in sexual or romantic relationships, but this is not the case. In recent years, small studies have suggested that autistic individuals are more likely to experience a wider diversity of sexual orientations and are less likely to have sexually transmitted infections (STIs). However, the existing evidence has been limited in size and scope.

In the largest study to date on these topics, the team at the Autism Research Center used an anonymous, self-report survey to study the sexual activity, sexual orientation, and sexual health of autistic adults. Overall, 1,183 autistic and 1,203 non-autistic adolescents and adults (aged 16-90 years) provided information about their sexual activity, sexual orientation, and medical history of STIs.

The results showed that the majority of autistic adults (70% of autistic males and 76% of autistic females) engage in sexual activity—although they do so to a lesser degree than their non-autistic peers (89% of both non-autistic males and females report engaging in sexual activity). In contrast to previous findings, the results also found that there were no differences in likelihood of ever contracting an STI, or the age at which participants first engaged in sexual activity, between autistic and non-autistic individuals.

In addition, the study found that autistic adults and adolescents are approximately eight times more likely to identify as asexual and ‘other’ sexuality than their non-autistic peers. And there were sex differences in sexual orientation: autistic males are 3.5 times more likely to identify as bisexual than non-autistic males, whereas autistic females are three times more likely to identify as homosexual than autistic females.

When comparing autistic females and males directly, autistic females were more likely to be sexually active; more likely to identify as asexual, bisexual, and ‘other’ sexuality; and were less likely to identify as heterosexual.

Elizabeth Weir, a PhD candidate at the Autism Research Center in Cambridge, and the lead researcher of the study, said: “Understanding the intersectional identities of autistic individuals who are asexual, bisexual, homosexual, or ‘other’ sexuality is key. It is particularly important that healthcare providers and educators use language that is affirming and accepting of all sexual orientations and gender identities when providing sexual education and sexual health screening checks to autistic and non-autistic people alike.” 

Dr Carrie Allison, Director of Strategy at the Autism Research Center and a member of the team, said: “We must ensure that autistic individuals are receiving equal access to healthcare and support in their choices in their personal lives, to enjoy fulfilling lives and good mental health.”

Professor Simon Baron-Cohen, Director of the Autism Research Center and a member of the team, said: “This new study is an important example of applied health research with policy relevance for health and social care services.”

Source/Credit: University of Cambridge

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Pandemic Has Triggered a Cycle of Mental Health Struggles and Physical Inactivity

Photo by Liza Summer from Pexels

 A large, multi-state study highlights how the COVID-19 pandemic has created a cyclical public health problem by both exacerbating mental health challenges and making it more difficult for people to maintain physical activity. The study also reveals that lower-income households struggled more with both mental health challenges and maintaining physical activity levels.

“We know that physical activity is important for helping people maintain their mental health, but this study reveals the unforgiving cycle that the pandemic has imposed on many people,” says Lindsey Haynes-Maslow, co-author of the study and an associate professor of agricultural and human sciences at North Carolina State University.

“The pandemic has increased psychological distress, which makes it more difficult for people to maintain their physical activity levels. This, in turn, further hurts their mental health, which makes them less likely to be active, and so on. Once you get on this roller coaster ride, it’s hard to get off. And all of this is exacerbated by the pandemic making it harder for people to find safe spaces in which to exercise.”

For this study researchers were focused on two questions: How is the pandemic influencing physical activity and mental health status? And how, if at all, do physical activity and mental health status relate to each other?

To address those questions, the researchers conducted an in-depth, online survey of 4,026 adults in Louisiana, Montana, North Carolina, Oregon and West Virginia. The survey was conducted between April and September of 2020.

The researchers found that the more physically active people were, the better their mental health status. That held true even when accounting for an individual’s race/ethnicity, household income and other socioeconomic demographic variables.

Treatments that may protect eggs against ageing

 

The spindle is responsible for separating the chromosomes equally when the oocyte goes through specialist meiotic cell divisions. The spindle is made of fibers called microtubules (green) to which the chromosomes (red) are attached. The use of MitoQ or BGP-15 improves the organization of the microtubules and alignment of the chromosomes to the center of the spindle. The oocyte has an improved chance of properly separating chromosomes and thereby avoiding aneuploidy when the egg is activated by the fertilizing sperm.

A woman’s fertility decreases as she ages – largely because of fewer healthy oocytes or eggs, and those that are available for fertilization often have chromosomal abnormalities which result in a higher incidence of miscarriage and genetic disorders such as Down’s syndrome.

Now a team at the Monash Biomedicine Discovery Institute (BDI) and Robinson Research Institute, collaborating with Monash IVF, has found a potential treatment that targets mitochondria to help prevent these chromosomal errors in mouse and human eggs.

In a paper published in the journal Human Reproduction, researchers led by Professors John Carroll and Rebecca Robker used two mitochondria-targeted therapeutics – called MitoQ and BGP-15 – which appeared to protect eggs from the chromosomal disturbances seen in older or abnormal eggs.

In particular, the addition of these agents improved how immature human eggs organize their chromosomes when matured in laboratory conditions. If this effect holds true for eggs maturing in the body it may also prevent chromosomal abnormalities in human eggs, effectively protecting them against miscarriage or genetic consequences such as Down’s syndrome.

The first author, Dr Usama Al-Zubaidi from the Monash BDI says: “Given that increasing numbers of women delay childbearing there is an imperative to improve fertility and reduce miscarriage and chromosomal anomalies associated with maternal ageing.”

The study identified “two excellent candidates that may one day help to improve fertility in older women.”

The age-related decline in fertility is strongly attributed to ovarian ageing, diminished ovarian reserves, and a decline in oocyte quality. One cause of this is due to increased oxidative stress within the oocytes.

Mitochondria – whether in an oocyte or any other cell in the body - use oxygen to create energy and one of the by-products is the production of free radicals. Oocytes are made during fetal life so have a lot of time to accumulate oxidative damage. Also, as eggs age, their defenses against oxidative damage become compromised. MitoQ and BGP-15 appear to be protecting eggs at least in part by improving mitochondrial function and minimizing oxidative stress during critical periods when the eggs are dividing their chromosomes.

Next steps involve finding the best conditions for these therapies to work when eggs are maturing inside the ovary and if the effects seen on chromosome organization translate into healthier eggs that have a better chance to develop into healthy pregnancies.

“Increasingly, fertility science is turning to therapies that specifically target these mitochondria with a view to preventing the chromosomal abnormalities that occur due to ageing and oxidative stress,” Professor Carroll said.

“Our study looked at two of these candidates to see whether they in fact made a difference to older eggs from humans and mice and found they can make the older eggs ‘younger’ again.” They were very effective at one level, but we are now working on seeing if this approach can work in patients.”

Both MitoQ and BGP-15 are used in humans already, – with MitoQ used to treat age associated hypertension while BGP-15 has been used in clinical trials for diabetes where it was given orally.

Medical Director Monash IVF, Professor Luk Rombauts said that improving function of the mitochondria, which he calls “the little energy factories within the eggs”, is one of the potential strategies to enhance egg quality and reproductive success, even more so in older women. “Monash IVF is keen to continue its collaboration with Professor John Carroll’s lab to find meaningful ways to turn this research into new treatment strategies.”

Source/Credit: Monash University

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Plasma doesn’t help severely ill COVID-19 patients

 

Giving severely ill COVID-19 patients a transfusion of blood from donors who have already recovered from the virus did not help them improve — and in some cases made them sicker, according to a major Canadian-led clinical trial reporting results in Nature Medicine.

“Convalescent plasma had been found to boost immunity in patients infected with some other viral entities, including SARS, in the past,” said local principal investigator Susan Nahirniak, professor of laboratory medicine and pathology in the University of Alberta’s Faculty of Medicine & Dentistry and medical/scientific lead for the Alberta Precision Laboratories transfusion and transplantation medicine program.

“But this trial did not demonstrate any benefit in terms of changing the course for patients who were admitted to hospital needing oxygen for SARS-CoV-2,” Nahirniak said. “It did not prevent intubation or death.”

The randomized controlled study followed 921 COVID-19 patients in Canada, the United States and Brazil who were admitted to hospital within 12 days of the onset of their respiratory symptoms. Two-thirds (614 patients) received convalescent plasma transfusions and one-third (307 patients) did not.

Of the convalescent plasma group, 199 of the patients required intubation or died, while 86 patients in the control group had these outcomes. Patients in the convalescent arm also experienced more serious adverse events such as needing more oxygen or worsening respiratory failure. The trial was terminated early when researchers realized the outcomes were not positive.

Varying immune responses

Another finding of the trial was that the level of neutralizing antibodies, or titres, in the blood of recovered COVID-19 patients was highly variable, which may have implications for how the population responds to vaccination.

“We were finding that several of the people who had signed up as donors were dropping their titres fairly quickly, so maintaining that donor pool was a challenge,” said Nahirniak. 

“It is proof that just because you’ve had COVID once doesn’t mean you can’t have it again,” she said. “It reinforces the need to be vigilant and possibly give boosters, similar to what we do with influenza.”

At the same time, the research team found that some donors had higher levels of non-functional antibodies against the virus’s spike protein. They reported that recipients of this plasma seemed to have poorer outcomes and recommended continued research on the prevalence and impact of these antibodies.

“If COVID is part of our lives going forward and there are certain antibodies that could be potentially harmful, is that something we need to be testing for and screening out for plasma donors?” Nahirniak posited.

Nahirniak noted that participating in the trial during the early days of the COVID-19 pandemic, when few treatments had been identified, helped to boost morale for both patients and clinical staff.

“We felt like we could do nothing, so at least this was an option, identifying the patients early on and getting them monitored.”

Nahirniak noted she was surprised by the disappointing results, but “that’s why we do a trial — we anticipated better success against the virus.”

The study was funded by the Canadian Institutes of Health Research and numerous local health agencies, including the University of Alberta Hospital Foundation and Alberta Health Services.

Source/Credit: University of Alberta

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Targeting tickborne diseases

"Benedict Khoo" Source: University of Minnesota

For Benedict Khoo, making a breakthrough discovery in health-related research doesn’t mean much if it can’t be put to use bettering people’s lives.

For Benedict Khoo, making a breakthrough discovery in health-related research doesn’t mean much if it can’t be put to use bettering people’s lives.

He knows from experience. When he worked in a research lab in Ohio, he felt “divorced from having a tangible impact,” due largely to regulatory hurdles in the field.

But that all changed when he turned to public health. There, he says, however his work turns out, he learns something that could help people make their own health decisions or influence policies. 

“That’s what drove me—to have that impact on the world and feel like I’m doing something,” says Khoo, a doctoral student in the School of Public Health (SPH). 

He found his niche with Jonathan Oliver, an assistant professor of environmental health sciences in SPH, who is now his adviser. Together they study the prevalence of Lyme disease and other tickborne diseases of humans, in a study area comprising Minnesota and adjacent northern Iowa and western Wisconsin. 

How a plant virus could protect and save your lungs from metastatic cancer

 

Nanoparticles engineered from the cowpea mosaic virus have shown efficacy
in treating and greatly reducing the spread of metastatic cancers in the lungs of mice.

Using a virus that grows in black-eyed pea plants, nanoengineers at the University of California San Diego developed a new treatment that could keep metastatic cancers at bay from the lungs. The treatment not only slowed tumor growth in the lungs of mice with either metastatic breast cancer or melanoma, it also prevented or drastically minimized the spread of these cancers to the lungs of healthy mice that were challenged with the disease.

The research was published in the journal Advanced Science.

Cancer spread to the lungs is one of the most common forms of metastasis in various cancers. Once there, it is extremely deadly and difficult to treat.

Researchers at the UC San Diego Jacobs School of Engineering developed an experimental treatment that combats this spread. It involves a bodily injection of a plant virus called the cowpea mosaic virus. The virus is harmless to animals and humans, but it still registers as a foreign invader, thus triggering an immune response that could make the body more effective at fighting cancer.

The idea is to use the plant virus to help the body’s immune system recognize and destroy cancer cells in the lungs. The virus itself is not infectious in our bodies, but it has all these danger signals that alarm immune cells to go into attack mode and search for a pathogen, said Nicole Steinmetz, professor of nanoengineering at UC San Diego and director of the university’s Center for Nano-ImmunoEngineering.

To draw this immune response to lung tumors, Steinmetz’s lab engineered nanoparticles made from the cowpea mosaic virus to target a protein in the lungs. The protein, called S100A9, is expressed and secreted by immune cells that help fight infection in the lungs. And there is another reason that motivated Steinmetz’s team to target this protein: overexpression of S100A9 has been observed to play a role in tumor growth and spread.

“For our immunotherapy to work in the setting of lung metastasis, we need to target our nanoparticles to the lung,” said Steinmetz. “Therefore, we created these plant virus nanoparticles to home in on the lungs by making use of S100A9 as the target protein. Within the lung, the nanoparticles recruit immune cells so that the tumors don’t take.”

“Because these nanoparticles tend to localize in the lungs, they can change the tumor microenvironment there to become more adept at fighting off cancer—not just established tumors, but future tumors as well,” said Eric Chung, a bioengineering Ph.D. student in Steinmetz’s lab who is one of the co-first authors on the paper.

To make the nanoparticles, the researchers grew black-eyed pea plants in the lab, infected them with cowpea mosaic virus, and harvested the virus in the form of ball-shaped nanoparticles. They then attached S100A9-targeting molecules to the surfaces of the particles.

The researchers performed both prevention and treatment studies. In the prevention studies, they first injected the plant virus nanoparticles into the bloodstreams of healthy mice, and then later injected either triple negative breast cancer or melanoma cells in these mice. Treated mice showed a dramatic reduction in the cancers spreading to their lungs compared to untreated mice.

In the treatment studies, the researchers administered the nanoparticles to mice with metastatic tumor in their lungs. These mice exhibited smaller lung tumors and survived longer than untreated mice.

What’s remarkable about these results, the researchers point out, is that they show efficacy against extremely aggressive cancer cell lines. “So, any change in survival or lung metastasis is pretty striking,” said Chung. “And the fact that we get the level of prevention that we do is really, really amazing.”

Steinmetz envisions that such a treatment could be especially helpful to patients after they have had a cancerous tumor removed. “It wouldn’t be meant as an injection that’s given to everyone to prevent lung tumors. Rather, it would be given to patients who are at high risk of their tumors growing back as a metastatic disease, which often manifests in the lung. This would offer their lungs protection against cancer metastasis,” she said.

Before the new treatment can reach that stage, the researchers need to do more detailed immunotoxicity and pharmacology studies. Future studies will also explore combining this with other treatments such as chemotherapy, checkpoint drugs or radiation.

Source/Credit: UC San Diego Jacobs School of Engineering

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Black Hole Snacks on a Star

 

This illustration shows a glowing stream of material from a star, torn to shreds as it was being devoured by a supermassive black hole. The feeding black hole is surrounded by a ring of dust, not unlike the plate of a toddler is surrounded by crumbs after a meal. NASA/JPL-Caltech

While black holes and toddlers don't seem to have much in common, they are remarkably similar in one aspect: Both are messy eaters, generating ample evidence that a meal has taken place.

But whereas one might leave behind droppings of pasta or splatters of yogurt, the other creates an aftermath of mind-boggling proportions. When a black hole gobbles up a star, it produces what astronomers call a "tidal disruption event." The shredding of the hapless star is accompanied by an outburst of radiation that can outshine the combined light of every star in the black hole's host galaxy for months, even years. 

In a paper published in The Astrophysical Journal, a team of astronomers led by Sixiang Wen, a postdoctoral research associate at the University of Arizona Steward Observatory, use the X-rays emitted by a tidal disruption event known as J2150 to make the first measurements of both the black hole's mass and spin. This black hole is of a particular type – an intermediate-mass black hole – which has long eluded observation.

"The fact that we were able to catch this black hole while it was devouring a star offers a remarkable opportunity to observe what otherwise would be invisible," said Ann Zabludoff, UArizona professor of astronomy and co-author on the paper. "Not only that, by analyzing the flare we were able to better understand this elusive category of black holes, which may well account for the majority of black holes in the centers of galaxies."

Study links severe COVID-19 to increase in self-attacking antibodies

 

Hospitalized COVID-19 patients are substantially more likely to harbor autoantibodies — antibodies directed at their own tissues or at substances their immune cells secrete into the blood — than people without COVID-19, according to a new study.

Autoantibodies can be early harbingers of full-blown autoimmune disease.

“If you get sick enough from COVID-19 to end up in the hospital, you may not be out of the woods even after you recover,” said PJ Utz, MD, professor of immunology and rheumatology at Stanford Medicine.

Utz shares senior authorship of the study, which was published Sept. 14 in Nature Communications, with Chrysanthi Skevaki, MD, PhD, instructor of virology and laboratory medicine at Philipps University Marburg in Germany, and Eline Luning Prak, MD, PhD, professor of pathology and laboratory medicine at the University of Pennsylvania. The study’s lead authors are Sarah Chang, a former technician in Utz’s lab; recent Stanford undergraduate Allen Feng, now a technician in the Utz lab; and senior research investigator Wenshao Meng, PhD, and postdoctoral scholar Sokratis Apostolidis, MD, both at the University of Pennsylvania.

The scientists looked for autoantibodies in blood samples drawn during March and April of 2020 from 147 COVID-19 patients at the three university-affiliated hospitals and from a cohort of 48 patients at Kaiser Permanente in California. Blood samples drawn from other donors prior to the COVID-19 pandemic were used as controls.

The researchers identified and measured levels of antibodies targeting the virus; autoantibodies; and antibodies directed against cytokines, proteins that immune cells secrete to communicate with one another and coordinate their overall strategy.

Upward of 60% of all hospitalized COVID-19 patients, compared with about 15% of healthy controls, carried anti-cytokine antibodies, the scientists found. This could be the result of immune-system overdrive triggered by a virulent, lingering infection. In the fog of war, the abundance of cytokines may trip off the erroneous production of antibodies targeting them, Utz said.

If any of these antibodies block a cytokine’s ability to bind to its appropriate receptor, the intended recipient immune cell may not get activated. That, in turn, might buy the virus more time to replicate and lead to a much worse outcome.