The Drugmaker Merck Says Its Antiviral Pill Is Effective Against Coronavirus

The drug maker says its pill was shown in a clinical trial to cut the risk of hospitalization or death from the virus in half. Australia is accelerating plans to ease international travel restrictions for its citizens and permanent residents.

The drug maker Merck said on Friday that it would seek authorization for the first antiviral pill for Covid after its drug, known as molnupiravir, was shown in a clinical trial to cut the risk of hospitalization or death in half when given to high-risk people early in their infections.

The treatment could become the first in a wave of antiviral pill products, which experts say could offer a powerful new tool in efforts to tame the pandemic, as they could reach more people than the antibody treatments that are being widely used in the United States for similar patients.

I think it will translate into many thousands of lives being saved worldwide, where there’s less access to monoclonal antibodies, and in this country, too,” said Dr. Robert Shafer, an infectious disease specialist and expert on antiviral therapy at Stanford University.

Late-stage study results of two other antiviral pills, one developed by Pfizer and the other by Atea Pharmaceuticals and Roche, are expected within the next few months.

The Merck drug, which is designed to stop the coronavirus from replicating, is to be taken as four capsules twice a day for five days.

Merck said an independent board of experts monitoring its study data had recommended that its trial be stopped early because the drug’s benefit to patients had proved so convincing. The company said that the Food and Drug Administration had agreed with that decision.

For the research, the monitors looked at data through early August, when the study had enrolled 775 volunteers in the United States and overseas. For volunteers who received the drug, their risk of being hospitalized or dying fell 50 percent, without any concerning side effects, compared with those who received placebo pills, Merck said in a news release announcing the findings.

Seven percent of volunteers in the group that received the drug were hospitalized, and none of them died, compared with a 14 percent rate of hospitalization and death — including eight deaths — in the group that received the placebo.

The Merck pill’s efficacy was lower than that of monoclonal antibody treatments, which mimic antibodies that the immune system generates naturally when fighting the virus. Those drugs have been in high demand recently, but they are expensive, are typically given intravenously, and have proved cumbersome and labor-intensive for hospitals and clinics to administer. Studies have shown that they reduce hospitalizations and deaths 70 to 85 percent in similar high-risk Covid patients.

Source: https://www.nytimes.com/

3 Existing Drugs Fight Coronavirus with ‘almost 100%’ Success

Israeli scientists say they have identified three existing drugs that have good prospects as COVID-19 treatments, reporting that they illustrated high ability to fight the virus in lab tests.

They placed the substances with live SARS‑CoV‑2 and human cells in vitro. The results “showed that the drugs can protect cells from onslaught by the virus with close to 100 percent effectiveness, meaning that almost 100% of the cells lived despite being infected by the virus,” Prof. Isaiah Arkin, the Hebrew University biochemist behind the research, told The Times of Israel.

By contrast, in normal circumstances, around half the cells would have died after two days following contact with the virus.” He added there are strong indications that the drugs will be robust against changing variants.

Arkin, part of a Hebrew University center that specializes in repurposing existing drugs, said that he screened more than 3,000 medicines for suitability, in what he describes as a needle-in-a-haystack search. This approach can provide a fast track to find treatments as the drugs have already been tried and tested, and he hopes to work with a pharmaceutical company to quickly get the medicines he identified clinically tested for COVID-19.

We have the vaccine, but we shouldn’t rest on our laurels, and I would like to see these drugs become part of the arsenal that we use to fight the coronavirus,” he said. When confronting SARS‑CoV‑2, the drugs in question — darapladib, which currently treats atherosclerosis; the cancer drug Flumatinib; and an HIV medicine — don’t target the spike protein. Rather, they target one of two other proteins: the envelope protein and the 3a protein. These proteins — especially the envelope proteinhardly change between variants, and even between diseases from the coronavirus family. As such, drugs that target them are likely to remain effective in spite of mutations, Arkin said.

Source: https://www.timesofisrael.com/

FDA-approved Drugs Slow or Reverse Alzheimer’s

A research team at Washington University School of Medicine in St. Louis has identified potential new treatment targets for Alzheimer’s disease, as well as existing drugs that have therapeutic potential against these targets.

The potential targets are defective proteins that lead to the buildup of amyloid in the brain, contributing to the onset of problems with memory and thinking that are the hallmark of Alzheimer’s. The 15 existing drugs identified by the researchers have been approved by the Food and Drug Administration (FDA) for other purposes, providing the possibility of clinical trials that could begin sooner than is typical, according to the researchers.

In addition, the experiments yielded seven drugs that may be useful for treating faulty proteins linked to Parkinson’s disease, six for stroke and one for amyotrophic lateral sclerosis (ALS).

Scientists have worked for decades to develop treatments for Alzheimer’s by targeting genes rooted in the disease process but have had little success. That approach has led to several dead ends because many of those genes don’t fundamentally alter proteins at work in the brain. The new study takes a different approach, by focusing on proteins in the brain, and other tissues, whose function has been altered.

In this study, we used human samples and the latest technologies to better understand the biology of Alzheimer’s disease,” said principal investigator Carlos Cruchaga, the Reuben Morriss III Professor of Neurology and a professor of psychiatry. “Using Alzheimer’s disease samples, we’ve been able to identify new genes, druggable targets and FDA-approved compounds that interact with those targets to potentially slow or reverse the progress of Alzheimer’s.”

The scientists focused on protein levels in the brain, cerebrospinal fluid (CSF) and blood plasma of people with and without Alzheimer’s disease. Some of the proteins were made by genes previously linked to Alzheimer’s risk, while others were made by genes not previously connected to the disease. After identifying the proteins, the researchers compared their results to several databases of existing drugs that affect those proteins.

The new study, funded by the National Institute on Aging of the National Institutes of Health (NIH), is published in the journal Nature Neuroscience.

Source: https://source.wustl.edu/

AI Recognises the Biological Activity of Natural Products

Nature has a vast store of medicinal substances. “Over 50 percent of all drugs today are inspired by nature,” says Gisbert Schneider, Professor of Computer-​Assisted Drug Design at ETH Zurich. Nevertheless, he is convinced that we have tapped only a fraction of the potential of natural products. Together with his team, he has successfully demonstrated how artificial intelligence (AI) methods can be used in a targeted manner to find new pharmaceutical applications for natural products. Furthermore, AI methods are capable of helping to find alternatives to these compounds that have the same effect but are much easier and therefore cheaper to manufacture.

And so the ETH researchers are paving the way for an important medical advance: we currently have only about 4,000 basically different medicines in total. In contrast, estimates of the number of human proteins reach up to 400,000, each of which could be a target for a drug. There are good reasons for Schneider’s focus on nature in the search for new pharmaceutical agents.

Most natural products are by definition potential active ingredients that have been selected via evolutionary mechanisms,” he says.
Whereas scientists used to trawl collections of natural products on the search for new drugs, Schneider and his team have flipped the script: first, they look for possible target molecules, typically proteins, of natural products so as to identify the pharmacologically relevant compounds. “The chances of finding medically meaningful pairs of active ingredient and target protein are much greater using this method than with conventional screening,” Schneider says.

Source: https://www.weforum.org/

Targeted delivery of therapeutic RNAs directly to cancer cells

Tel Aviv University‘s groundbreaking technology may revolutionize the treatment of cancer and a wide range of diseases and medical conditions. In the framework of this study, the researchers were able to create a new method of transporting RNA-based drugs to a subpopulation of immune cells involved in the inflammation process, and target the disease-inflamed cell without causing damage to other cells.

The study was led by Prof. Dan Peer, a global pioneer in the development of RNA-based therapeutic delivery. He is Tel Aviv University‘s Vice President for Research and Development, head of the Center for Translational Medicine and a member of both the Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, and the Center for Nanoscience and Nanotechnology. The study was published in the prestigious scientific journal Nature Nanotechnology.

Our development actually changes the world of therapeutic antibodies. Today we flood the body with antibodies that, although selective, damage all the  that express a specific receptor, regardless of their current form. We have now taken out of the equation  that can help us, that is, uninflamed cells, and via a simple injection into the bloodstream can silence, express or edit a particular gene exclusively in the cells that are inflamed at that given moment,” explains Prof. Peer.

As part of the study, Prof. Peer and his team were able to demonstrate this groundbreaking development in animal models of inflammatory bowel diseases such as Crohn’s disease and colitis, and improve all inflammatory symptoms, without performing any manipulation on about 85% of the immune system cells. Behind the innovative development stands a simple concept, targeting to a specific receptor conformation. “On every cell envelope in the body, that is, on the , there are receptors that select which substances enter the cell,” explains Prof. Peer. “If we want to inject a drug, we have to adapt it to the specific receptors on the , otherwise it will circulate in the bloodstream and do nothing. But some of these receptors are dynamic—they change shape on the membrane according to external or internal signals. We are the first in the world to succeed in creating a drug delivery system that knows how to bind to receptors only in a certain situation, and to skip over the other identical cells, that is, to deliver the drug exclusively to cells that are currently relevant to the disease.”

Source: https://phys.org/

Simple Diagnostic Tool Predicts Individual Risk of Alzheimer’s

Researchers at Lund University in Sweden have developed an algorithm that combines data from a simple blood test and brief memory tests, to predict with great accuracy who will develop Alzheimer’s disease in the future.

Approximately 20-30% of patients with Alzheimer’s disease are wrongly diagnosed within specialist healthcare, and diagnostic work-up is even more difficult in primary care. Accuracy can be significantly improved by measuring the proteins tau and beta-amyloid via a spinal fluid sample, or PET scan. However, those methods are expensive and only available at a relatively few specialized memory clinics worldwide. Early and accurate diagnosis of AD is becoming even more important, as new drugs that slow down the progression of the disease will hopefully soon become available.

A research group led by Professor Oskar Hansson at Lund University have now shown that a combination of relatively easily acccessible tests can be used for early and reliable diagnosis of Alzheimer’s disease. The study examined 340 patients with mild memory impairment in the Swedish BioFINDER Study, and the results were confirmed in a North American study of 543 people.

A combination of a simple blood test (measuring a variant of the tau protein and a risk gene for Alzheimer’s) and three brief cognitive tests that only take 10 minutes to complete, predicted with over 90% certainty which patients would develop Alzheimer’s dementia within four years. This simple prognostic algorithm was significantly more accurate than the clinical predictions by the dementia experts who examined the patients, but did not have access to expensive spinal fluid testing or PET scans, said Oskar Hansson.

Our algorithm is based on a blood analysis of phosphylated tau and a risk gene for Alzheimer’s, combined with testing of memory and executive function. We have now developed a prototype online tool to estimate the individual risk of a person with mild memory complaints developing Alzheimer’s dementia within four years”, explains Sebastian Palmqvist, first author of the study and associate professor at Lund University.

One clear advantage of the algorithm is that it has been developed for use in clinics without access to advanced diagnostic instruments. In the future, the algorithm might therefore make a major difference in the diagnosis of Alzheimer’s within primary healthcare.

The algorithm has currently only been tested on patients who have been examined in memory clinics. Our hope is that it will also be validated for use in primary healthcare as well as in developing countries with limited resources”, says Sebastian Palmqvist.

Simple diagnostic tools for Alzheimer’s could also improve the development of drugs, as it is difficult to recruit the suitable study partcipants for drug trials in a time- and cost-effective manner. ”The algorithm will enable us to recruit people with Alzheimer’s at an early stage, which is when new drugs have a better chance of slowing the course of the disease”, concludes Professor Oskar Hansson.

The findings are published in Nature Medicine.

Source: https://www.lunduniversity.lu.se/

AI Makes Gigantic Leap And Heralds A Revolution In Biology

An artificial intelligence (AI) network developed by Google AI offshoot DeepMind has made a gargantuan leap in solving one of biology’s grandest challengesdetermining a protein’s 3D shape from its amino-acid sequence.

DeepMind’s program, called AlphaFold, outperformed around 100 other teams in a biennial protein-structure prediction challenge called CASP, short for Critical Assessment of Structure Prediction. The results were announced on 30 November, at the start of the conference — held virtually this year — that takes stock of the exercise.

A protein’s function is determined by its 3D shape

This is a big deal,” says John Moult, a computational biologist at the University of Maryland in College Park, who co-founded CASP in 1994 to improve computational methods for accurately predicting protein structures. “In some sense the problem is solved.

The ability to accurately predict protein structures from their amino-acid sequence would be a huge boon to life sciences and medicine. It would vastly accelerate efforts to understand the building blocks of cells and enable quicker and more advanced drug discovery.

AlphaFold came top of the table at the last CASP — in 2018, the first year that London-based DeepMind participated. But, this year, the outfit’s deep-learning network was head-and-shoulders above other teams and, say scientists, performed so mind-bogglingly well that it could herald a revolution in biology.

It’s a game changer,” says Andrei Lupas, an evolutionary biologist at the Max Planck Institute for Developmental Biology in Tübingen, Germany, who assessed the performance of different teams in CASP. AlphaFold has already helped him find the structure of a protein that has vexed his lab for a decade, and he expects it will alter how he works and the questions he tackles. “This will change medicine. It will change research. It will change bioengineering. It will change everything,” Lupas adds.

Source: https://www.nature.com/

Bringing drugs to the brain to treat neurodegenerative diseases

The blood-brain barrier is the main obstacle in treating neurodegenerative diseases such as Alzheimer and Parkinson. According to a recent study conducted by Jean-Michel Rabanel, a postdoctoral researcher under the supervision of Professor Charles Ramassamy, nanoparticles with specific properties could cross this barrier and be captured by neuronal cells. Researchers are confident that these results will open important prospects for releasing drugs directly to the brain. This breakthrough finding would enable improved treatment for neurodegenerative diseases affecting more than 565,000 Canadians, including 141,000 Quebecers.

The blood-brain barrier filters out harmful substances to prevent them from freely reaching the brain. But this same barrier also blocks the passage of drugs,” explains the pharmacologist Charles Ramassamy. Typically, high doses are required to get a small amount of the drug into the brain. What remains in the bloodstream has significant side effects. Often, this discomfort leads the patient to stop the treatment.  The use of nanoparticles, which encapsulate the drugs, would result in fewer collateral side effects while increasing brain efficiency.

To prove the effectiveness of this method, the research team first tested it on cultured cells, then on zebrafish. “This species offers several advantages. Its blood-brain barrier is similar to that of humans and its transparent skin makes it possible to see nanoparticles’ distribution almost in real time,” says Professor Ramassamy, Chairholder of the Louise and André Charron Research Chair on Alzheimer’s disease, from the Fondation Armand-Frappier.

Using in vivo tests, researchers were able to observe the crossing of the blood-brain barrier. They also confirmed the absence of toxicity in the library of selected nanoparticles. “We made the particles with polylactic acid (PLA), a biocompatible material that is easily eliminated by the body. A layer of polyethylene glycol (PEG) covers these nanoparticles and makes them invisible to the immune system, so they can longer circulate in the bloodstream,” he explains.

The findings have been published in the Journal of Controlled Release.

http://www.inrs.ca

All-Terrain NanoRobot Flips Through A Live Colon

A rectangular robot as tiny as a few human hairs can travel throughout a colon by doing back flips, Purdue University engineers have demonstrated in live animal models. Why the back flips? Because the goal is to use these robots to transport drugs in humans, whose colons and other organs have rough terrain. Side flips work, too. Why a back-flipping robot to transport drugs? Getting a drug directly to its target site could remove side effects, such as hair loss or stomach bleeding, that the drug may otherwise cause by interacting with other organs along the way.

The study, published in the journal Micromachines, is the first demonstration of a microrobot tumbling through a biological system in vivo. Since it is too small to carry a battery, the microrobot is powered and wirelessly controlled from the outside by a magnetic field.


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When we apply a rotating external magnetic field to these robots, they rotate just like a car tire would to go over rough terrain,” said David Cappelleri, a Purdue associate professor of mechanical engineering. “The magnetic field also safely penetrates different types of mediums, which is important for using these robots in the human body.

The researchers chose the colon for in vivo experiments because it has an easy point of entry – and it’s very messy. “Moving a robot around the colon is like using the people-walker at an airport to get to a terminal faster. Not only is the floor moving, but also the people around you,” said Luis Solorio, an assistant professor in Purdue’s Weldon School of Biomedical Engineering. “In the colon, you have all these fluids and materials that are following along the path, but the robot is moving in the opposite direction. It’s just not an easy voyage.

But this magnetic microrobot can successfully tumble throughout the colon despite these rough conditions, the researchers’ experiments showed. The team conducted the in vivo experiments in the colons of live mice under anesthesia, inserting the microrobot in a saline solution through the rectum. They used ultrasound equipment to observe in real time how well the microrobot moved around.

Source: https://www.purdue.edu/

Antibodies + Immunotherapy Result In Complete Elimination Of Tumors

Immunotherapy has revolutionized cancer treatment by stimulating the patient’s own immune system to attack cancer cells, yielding remarkably quick and complete remission in some cases. But such drugs work for less than a quarter of patients because tumors are notoriously adept at evading immune assault.

A new study in mice by researchers at Washington University School of Medicine in St. Louis has shown that the effects of a standard immunotherapy drug can be enhanced by blocking the protein TREM2, resulting in complete elimination of tumors. The findings, which are published in the journal Cell, point to a potential new way to unlock the power of immunotherapy for more cancer patients.

Immune cells infiltrate a human tumor in the four colorized images above. In a mouse study, researchers at Washington University School of Medicine in St. Louis have found that an antibody that targets the protein TREM2 empowers tumor-destroying immune cells and improves the effectiveness of cancer immunotherapy.

Essentially, we have found a new tool to enhance tumor immunotherapy,” said senior author Marco Colonna, MD, the Robert Rock Belliveau, MD, Professor of Pathology. “An antibody against TREM2 alone reduces the growth of certain tumors, and when we combine it with an immunotherapy drug, we see total rejection of the tumor. The nice thing is that some anti-TREM2 antibodies are already in clinical trials for another disease. We have to do more work in animal models to verify these results, but if those work, we’d be able to move into clinical trials fairly easily because there are already a number of antibodies available.”

T cells, a kind of immune cell, have the ability to detect and destroy tumor cells. To survive, tumors create a suppressive immune environment in and around themselves that keeps T cells subdued. A type of immunotherapy known as checkpoint inhibition wakes T cells from their quiescence so they can begin attacking the tumor. But if the tumor environment is still immunosuppressive, checkpoint inhibition alone may not be enough to eliminate the tumor.

An expert on the immune system, Colonna has long studied a protein called TREM2 in the context of Alzheimer’s disease, where it is associated with underperforming immune cells in the brain. Colonna and first author Martina Molgora, PhD, a postdoctoral researcher, realized that the same kind of immune cells, known as macrophages, also were found in tumors, where they produce TREM2 and promote an environment that suppresses the activity of T cells.

When we looked at where TREM2 is found in the body, we found that it is expressed at high levels inside the tumor and not outside of the tumor,” Colonna said. “So it’s actually an ideal target, because if you engage TREM2, you’ll have little effect on peripheral tissue.”

Colonna and Molgora — along with colleagues Robert D. Schreiber, PhD, the Andrew M. and Jane M. Bursky Distinguished Professor; and William Vermi, MD, an immunologist at the University of Brescia — set out to determine whether inhibiting TREM2 could reduce immunosuppression and boost the tumor-killing powers of T cells. As part of this study, the researchers injected cancerous cells into mice to induce the development of a sarcoma.

The mice were divided into four groups. In one group, the mice received an antibody that blocked TREM2; in another group, a checkpoint inhibitor; in the third group, both; and the fourth group, placebo. In the mice that received only placebo, the sarcomas grew steadily. In the mice that received the TREM2 antibody or the checkpoint inhibitor alone, the tumors grew more slowly and plateaued or, in a few cases, disappeared. But all of the mice that received both antibodies rejected the tumors completely. The researchers repeated the experiment using a colorectal cancer cell line with similarly impressive results.

Source: https://medicine.wustl.edu/