US targets mass virus vaccine campaign by year’s end

The United States hopes to begin a sweeping program of COVID vaccinations, reaching perhaps 20 million people by year’s end, top public health officials said Sunday as cases surge across the worst-hit nation.

The beginning of vaccinations could be a crucial turning point in the battle against the virus that has claimed more than 255,000 lives in the US, the world’s highest reported toll, since emerging from China late last year.

“Our plan is to be able to ship vaccines to the immunization sites within 24 hours of approval” by the US Food and Drug Administration, Moncef Slaoui, who heads the government’s coronavirus vaccine effort, told CNN.

He pointed to possible dates of December 11-12.

Slaoui estimated that 30 million people would be vaccinated per month starting in January.

‘Herd immunity’ by May?

But top US infectious disease official Anthony Fauci, who said “maybe 20 million people will be able to get vaccinated by the middle to the end December”, warned the situation could get worse before getting better if people fail to take precautions in the coming holiday season.

“We’re in a very difficult situation at all levels,” he told CBS’s “Face the Nation.”

With the Thanksgiving holiday on Thursday normally seeing a huge surge in travel, he said, “We’re really concerned” about “another spike in cases as we get colder and colder and colder into the December month—and then you start dealing with the Christmas holiday.”

FDA vaccine advisors are to meet December 10 to discuss approving vaccines which pharmaceutical firms Pfizer and Moderna say are at least 95 percent effective.

Slaoui said that by May, with potentially 70 percent of the population having been vaccinated, the country could attain “herd immunity,” meaning the virus can no longer spread widely and people can move closer to resuming their pre-coronavirus way of life.

But Fauci, separately, added a note of caution, saying herd immunity would come only if “you get an overwhelming majority of the people vaccinated with a highly efficacious vaccine.”

A recent Gallup poll showed that four in 10 Americans still say they would not get a COVID-19 vaccine, though that is down from five in 10 surveyed in September.

Officials have yet to announce which groups in the population would receive the vaccine first, though health care workers are certain to receive priority, followed by vulnerable groups like the elderly.

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Study identifies brain cells most affected by epilepsy and new targets for their treatment

Epilepsy is one of the most common neurological diseases. It is caused by a malfunction in brain cells and is usually treated with medicines that control or counteract the seizures.

Scientists from the Faculty of Health and Medical Sciences, University of Copenhagen and Rigshospitalet have now identified the exact neurons that are most affected by epilepsy. Some of which have never been linked to epilepsy before. The newfound neurons might contribute to epileptogenesis—the process by which a normal brain develops epilepsy—and could therefore be ideal treatment targets.

“Our findings potentially allows for the development of entirely new therapeutic approaches tailored towards specific neurons, which are malfunctioning in cases of epilepsy. This could be a breakthrough in personalized medicine-based treatment of patients suffering from epileptic seizures,” says Associate Professor Konstantin Khodosevich from Biotech Research & Innovation Center (BRIC), Faculty of Health and Medical Sciences.

A major step towards more effective drugs

It is the first time a study investigates how every single neuron in the epileptic zone of the human brain is affected by epilepsy. The researchers have analyzed more than 117,000 neurons, which makes it the largest single cell dataset for a brain disorder published so far.

Neurons have been isolated from tissue resected from patients being operated as part of the Danish Epilepsy Surgery Programme at Rigshospitalet in Copenhagen.

“These patients continue to have seizures despite the best possible combination of anti-seizure drugs. Unfortunately, this is the case for 30-40% of epilepsy patients. Active epilepsy imposes serious physical, cognitive, psychiatric and social consequences on patients and families. A more precise understanding of the cellular mechanism behind epilepsy could be a major step forward for developing drugs specifically directed against the epileptogenic process compared to the current mode of action reducing neuronal excitability in general throughout the brain’ says associate professor Lars Pinborg, head of the Danish Epilepsy Surgery Program at Rigshospitalet.

From ‘neuronal soup’ to single cell analysis

The study from the Khodosevich Group differs from previous work by using single cell analysis. Earlier studies on neuronal behavior in regards to epilepsy have taken a piece of the human brain and investigated all the neurons together as a group or a ‘neuronal soup.” When using this approach, diseased cells and healthy cells are mixed together, which makes it impossible to identify potential treatment targets.

“By splitting the neurons into many thousands of single cells, we can analyze each of them separately. From this huge number of single cells, we can pinpoint exactly what neurons are affected by epilepsy. We can even make a scale from least to most affected, which means that we can identify the molecules with the most promising potential to be effective therapeutic targets,” says Khodosevich.

Next step is to study the identified neurons and how their functional changes contribute to epileptic seizures. The hope is to then find molecules that can restore epilepsy related neuronal function back to normal and inhibit seizure generation.

Expanding knowledge on underlying mechanisms of epilepsy

The study confirms expression from key genes known from a number of previous studies, but is also a dramatic expansion of knowledge on the subject. Previously, gene expression studies have identified a couple of hundred genes that changes in epilepsy.

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Researchers discover new member of novel drug family for ‘undruggable’ targets

In the last several years, excitement has surged for a promising class of drugs that work not by inhibiting the action of a molecular target, as most conventional drugs do, but instead by harnessing the cell’s recycling system to destroy the target. However, these unusual compounds, known as molecular glue degraders, have been difficult to find and engineer.

Now, a research team led by scientists at the Broad Institute of MIT and Harvard and the Friedrich Miescher Institute for Biomedical Research in Basel, Switzerland has discovered a new molecular glue degrader called CR8. By dissecting the details of CR8’s molecular mechanism of action, as described in a paper published in Nature, the researchers show how it may be possible to build more of these unique compounds as potential treatments for a variety of diseases.

“We have shown that it is possible to take a conventional kinase inhibitor and, by attaching a particular chemical group, transform it into a molecular glue degrader,” said co-senior author Benjamin Ebert, an institute member in the Broad Cancer Program and the chair of the Department of Medical Oncology at Dana-Farber Cancer Institute. “This offers the potential for creating molecular glue degraders for a much wider range of therapeutic targets than we had initially anticipated.”

Throw away the lock and key

Most drugs use a lock-and-key approach to target proteins, typically enzymes, by directly binding within distinct grooves in the target protein to block its activity. Yet many other kinds of proteins, like transcription factors, lack such binding sites, which has stymied efforts to design drugs against these traditionally “undruggable” targets.

About six years ago, Ebert and his colleagues revealed that a well-known multiple myeloma drug, called lenalidomide, works as a molecular glue degrader. Instead of directly binding to its targets, it operates more stealthily, by recruiting a molecular machine that tags target proteins for destruction in the cell. This machine, known as E3 ubiquitin ligase, attaches a small protein called ubiquitin to the ill-fated targets, which are then degraded by the cell’s recycling system.

To identify more molecular glue degraders, Ebert’s team, led by co-first author Mikolaj Slabicki, a postdoctoral researcher at Broad and the German Cancer Research Center in Heidelberg, studied data on more than 4,500 drugs and compounds from the Broad’s Drug Repurposing Hub, a collection of compounds that have been shown to be safe in humans, including many that are FDA-approved. The scientists combed through these publicly available data to pinpoint drugs that preferentially kill cancer cells with high E3 ubiquitin ligase levels.

“We were always brainstorming in the lab to figure out how we can find more molecular glue degraders,” said Slabicki. “We were incredibly fortunate to have access to such large, robust datasets. We wouldn’t have made this discovery without the dataset generated at the Broad Cancer Program.”

A path to creating more

CR8 is a compound that was originally designed to inhibit enzymes called cyclin-dependent kinases (CDKs), which play important roles in controlling cell growth. The researchers used their bioinformatic approach to discover that CR8’s cell-killing activity correlates with levels of a component of the E3 ubiquitin ligase complex called DDB1.

The team found that CR8 kills cancer cells by inducing degradation of a protein called cyclin K, which is a binding partner of some CDKs, in particular CDK12. CR8 does this by acting like a molecular glue, binding CDK12-cyclin K, and recruiting DDB1 and subsequently other parts of the E3 ubiquitin ligase complex, which results in the tagging of cyclin K for degradation.

Collaborators from the Friedrich Miescher Institute including co-senior author Nicolas Thomä and co-first authors Zuzanna Kozicka and Georg Petzold solved the crystal structure of key components of this CR8-induced protein complex, which revealed new molecular details about the interactions between all the glued-together parts.

The Boston and Basel teams looked at the activity of a drug that’s structurally similar to CR8 and found that it doesn’t lead to cyclin K degradation. The only structural difference between the two compounds is a lone chemical moiety known as a pyridyl substituent, that protrudes out. This moiety, the team concluded, is sufficient to enable CR8 to act like a molecular glue degrader. The finding suggests that chemical modifications of outward-facing parts of inhibitors could turn them into molecular glue degraders of a given protein target.

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