Tag: medical treatments

Sirius helps reveal previously unknown process of maturation for key protein in SARS-CoV-2 replication

Sirius helps reveal previously unknown process of maturation for key protein in SARS-CoV-2 replication

Researchers at USP in São Carlos combined cutting-edge technologies and demonstrated that a molecule targeted by medications behaves differently than previously theorized.

A group of researchers from the University of São Paulo in São Carlos has just presented their findings from research indicating a new understanding of the maturation process and how inhibitors act upon the Mpro protein, an essential component in the life cycle of the Sars-CoV-2 virus and the target of various efforts to develop medications to treat Covid-19. Their results appear in an article entitled “An in-solution snapshot of SARS-COV-2 main protease maturation process and inhibition,” published in the journal Nature Communications (https://doi.org/10.1038/s41467-023-37035-5).

Mpro is an abbreviation for main protease, because of its importance to the virus. Today, two medications are available which interact with this molecule to treat covid-19. Still, some of the processes in this protein’s activity are not yet entirely understood, and this was the object of the study undertaken at Sirius.

As part of the role it plays in the life cycle of the Sars-CoV-2 virus, Mpro undergoes a series of modifications until it reaches its final form. Part of this process had already been described by the group from São Carlos, directed by Professor Glaucius Oliva.

André Godoy, who led the group, was one of the first external users of Sirius, the cutting- synchrotron light source planned and built by the Brazilian Center for Research in Energy and Materials (CNPEM), an organization overseen by the Ministry of Science, Technology and Innovation (MCTI).

In September 2020 he brought approximately 200 crystals containing proteins from the Sars-CoV-2 virus for analysis in the Manacá beamline, which was developed for experiments involving X-ray diffraction crystallography. “The Manacá beamline was the first research station to open at Sirius, as the result of a task-force effort at the CNPEM to support research exploring molecular mechanisms related to covid-19. This is one of the publications that resulted from this effort,” explains Harry Westfahl, Director of the Brazilian Synchrotron Light National Laboratory (LNLS).

Read more on the LNLS website

Image: Cryomicroscopy map of the Mpro dimer interacting with the N-terminal. Image obtained from analyses conducted at Diamond and Sirius by the USP São Carlos group

Unlocking the doors to effective COVID-19 treatments

Unlocking the doors to effective COVID-19 treatments

Developing therapeutics for COVID-19 should lessen the length and severity of the illness, keeping more people out of the hospital and improving patient outcomes.

A team of interdisciplinary researchers from the Institut National de la Recherche Scientifique (INRS) are hoping to identify effective COVID-19 therapeutics. With help from the Canadian Light Source (CLS) at the University of Saskatchewan, the team has been able to visualize the interaction between inhibitory molecules and viral proteins. This allows researchers to see if their drug designs work as intended.

“We have libraries of molecular fragments and drug candidates that we are testing,” said Michael Maddalena, a research intern in Steven LaPlante’s lab at INRS. “We are screening to see if they are active and actually stick to the virus’ proteins or to essential human receptors where we think there are opportunities for drugs.”

This research targets the proteins of the SARS-CoV-2 virus that are involved in its replication and survival. Their work also targets the essential human receptors that the virus depends on to enter human cells. Drugs that stick to human receptors are unlikely to be susceptible to viral mutants — ensuring that new therapeutics will be effective against new variants.

Read more on the CLS website

Image: The LaPlante research team

A promising treatment for ovarian cancer

A promising treatment for ovarian cancer

Scientists are looking to harness the immune system to fight cancer

Over 20,000 women across the U.S. and Canada are diagnosed with ovarian cancer annually. The symptoms of this disease are often overlooked until it has spread, making it difficult to detect and treat with conventional methods like radiation and chemotherapy.

Dr. Cory Books, Associate Professor in the Department of Chemistry and Biochemistry at California State University, Fresno, is looking to harness the immune system to fight cancer. He is interested in a particular protein, called mucin, that is found throughout the body and is involved with the production of mucus. This protein is altered in cancer cells, which makes it a unique target for researchers.

“The cell stops adding sugars to the protein, so instead of having this mucus layer, now it has a solid protein layer, and cancer uses that to help spread itself through the body,” Brooks said.

This alteration helps ovarian cancer grow and spread, but it also leaves a signal that can help clinicians locate the cancer and kill it.

“What that means now is that there’s sort of this unique signature that we can target with antibodies to develop a new treatment for cancer,” Brooks said.

Researchers have been interested in this protein since the late 1980s but have never before been able to visualize how antibodies interact with the molecule.

With the help of the CMCF beamline at the Canadian Light Source (CLS) located at the University of Saskatchewan, Brooks and his team were able to see how antibodies bind to the protein for the first time.

Read more on the CLS website

Image: Brandy White, lead author on the study and graduate student with the Department of Chemistry and Biochemistry at California State University, Fresno.

Safely studying dangerous infections just got a lot easier

Safely studying dangerous infections just got a lot easier

An extremely fast new 3D imaging method can show how cells respond to infection and to possible treatments

To combat a pandemic, science needs to move quickly. With safe and effective vaccines now widely available and a handful of promising COVID-19 treatments coming soon, there’s no doubt that many aspects of biological research have been successfully accelerated in the past two years.

Now, researchers from Lawrence Berkeley National Laboratory (Berkeley Lab) and Heidelberg University in Germany have cranked up the speed of imaging infected cells using soft X-ray tomography, a microscopic imaging technique that can generate incredibly detailed, three-dimensional scans.

Their approach takes mere minutes to gather data that would require weeks of prep and analysis with other methods, giving scientists an easy way to quickly examine how our cells’ internal machinery responds to SARS-CoV-2, or other pathogens, as well as how the cells respond to drugs designed to treat the infection.

“Prior to our imaging technique, if one wanted to know what was going on inside a cell, and to learn what changes had occurred upon an infection, they’d have to go through the process of fixing, slicing, and staining the cells in order to analyze them by electron microscopy. With all the steps involved, it would take weeks to get the answer. We can do it in a day,” said project co-lead Carolyn Larabell, a Berkeley Lab faculty scientist in the Biosciences Area. “So, it really speeds up the process of examining cells, the consequences to infection, and the consequences of treating a patient with a drug that may or may not cure or prevent the disease.”

Taking cellular freeze frames

Larabell is a professor of anatomy at UC San Francisco and director of the National Center for X-Ray Tomography, a facility based at Berkeley Lab’s Advanced Light Source (ALS). The facility’s staff developed soft X-ray tomography (SXT) in the early 2000s to fill in the gaps left by other cellular imaging techniques. They currently offer the SXT to investigators worldwide and continue to refine the approach. As part of a study published in Cell Reports Methods late last year, she and three colleagues performed SXT on human lung cell samples prepared by their colleagues at Heidelberg University and the German Center for Infection Research.

Read more on the Berkeley Lab website

Image: Digital images of cells infected with SARS-CoV-2, created from soft X-ray tomography taken of chemically fixed cells at the Advanced Light Source

Credit: Loconte et al./Berkeley Lab

Light sources have demonstrated huge adaptability during the pandemic

Light sources have demonstrated huge adaptability during the pandemic

Johanna Hakanpää is the beamline scientist for P11, one of the macromolecular crystallography beamlines at PETRAIII at DESY in Hamburg. Originally from Finland, she studied chemistry and then did her masters and PhD work in protein crystallography. Johanna was drawn to the field because she wanted to understand how life really works. Supporting health related research is important to her and Johanna is especially inspired by her son who is a patient of celiac disease. Together they hope that one day, with the help of science, he will be able to eat normally without having to think about what is contained in his food. Johanna started her light source journey as a user and was really impressed by the staff scientists who supported her during her experiments. This led her to apply for a beamline scientist position and she successfully made the transition, learning the technical aspects of the beamlines on the job.

In her #LightSourceSelfie, Johanna highlights the adaptability of light sources during the pandemic as a key strength. Being part of a team that was able to keep the lights on for users via remote experiments is a reflection of the commitment that Johanna and her colleagues have when it comes to facilitating science. Thousands of staff at light sources all around the world have shown the same commitment, ensuring scientific advances can continue. This is particularly true for vital research on the SARS-CoV-2 virus itself. Learn more about this research here: https://lightsources.org/lightsource-research-and-sars-cov-2/

Developing pain medication with fewer side effects

Developing pain medication with fewer side effects

Opiates like morphine and codeine provide many patients with relief: from the ache felt after mild surgery to chronic pain experienced by cancer patients. However, this type of medication can cause multiple side effects and can lead to physical dependency with long-term use. Improving pain medication would help millions of people to have a better quality of life.

Dr. Ken Ng, a professor at the University of Windsor and adjunct professor at the University of Calgary (UCalgary), and Sam Carr, a PhD student from UCalgary, have been working with Dr. Peter Facchini’s group at UCalgary to better understand how natural opiates are produced. The team has narrowed their focus on one enzyme in the last stage of opiate assembly, a process that occurs naturally in the poppy plant.

“Imagine this sort of like an assembly line,” Carr said. “There are a lot of different steps in this specific pathway, and each enzyme contributes a different step from the starting product to the finished drug.”

Read more on the Canadian Light Source (CLS) website

Image: Structure of the enzyme studied, a molecule of codeine, and a seed capsule from an opium poppy.

Credit: Sam Carr.

Researchers search for clues to COVID-19 treatment

Researchers search for clues to COVID-19 treatment

Two groups of researchers drew on SLAC tools to better understand how to target a key part of the virus that causes COVID-19

Vaccination, masks and physical distancing help limit the spread of COVID-19 – but, researchers say, the disease is still going to infect people, and doctors are still going to need better medicines to treat patients. This may be especially true for cancer patients and other at-risk people who may lack a sufficiently strong immune system to benefit from the vaccine. 

Now, two teams working in part at the Department of Energy’s SLAC National Accelerator Laboratory have found some clues that could, down the road, lead to new COVID drugs. 

The researchers, from John Tainer’s lab at MD Anderson Cancer Center and James Fraser’s group at the University of California, San Francisco, focused on a molecular structure that is common to all coronaviruses but has proven especially troublesome in the case of the virus that causes COVID-19. The structure contributes both to the virus’s ability to replicate and to immune system overreactions that have proven particularly deadly.

The trouble, Fraser said, is that scientists don’t know what kinds of molecules would bind to the structure, known as the Nsp3 macrodomain, let alone how to combine such molecules to interfere with its deadly work. 

To remedy that problem, Fraser’s group screened several thousand molecules at facilities including SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL) to see where and how well the molecules bound to crystallized forms of Nsp3. The team combined those results with computer models to understand how the molecules might affect the structure of the macrodomain and whether they might help inhibit its function. 

Read more on the SLAC website

Science Begins at Brookhaven Lab’s New Cryo-EM Research Facility

Science Begins at Brookhaven Lab’s New Cryo-EM Research Facility

Brookhaven Lab’s Laboratory for BioMolecular Structure is now open for experiments with visiting researchers using two NY State-funded cryo-electron microscopes.

UPTON, NY—On January 8, 2021, the U.S. Department of Energy’s (DOE) Brookhaven National Laboratory welcomed the first virtually visiting researchers to the Laboratory for BioMolecular Structure (LBMS), a new cryo-electron microscopy facility. DOE’s Office of Science funds operations at this new national resource, while funding for the initial construction and instrument costs was provided by NY State. This state-of-the-art research center for life sciences imaging offers researchers access to advanced cryo-electron microscopes (cryo-EM) for studying complex proteins as well as the architecture of cells and tissues.

Many modern advances in biology, medicine, and biotechnology were made possible by researchers learning how biological structures such as proteins, tissues, and cells interact with each other. But to truly reveal their function as well as the role they play in diseases, scientists need to visualize these structures at the atomic level. By creating high-resolution images of biological structure using cryo-EMs, researchers can accelerate advances in many fields including drug discovery, biofuel development, and medical treatments.

Read more on the BNL website

Image: Brookhaven Lab Scientist Guobin Hu loaded the samples sent from researchers at Baylor College of Medicine into the new cryo-EM at LBMS.