Tag: SARS-CoV-2

Research finds possible key to long term COVID-19 symptoms

Research finds possible key to long term COVID-19 symptoms

Key Points

  • Researchers from La Trobe University have identified a key mechanism that may link COVID-19 infection and lung damage
  • Lung damage is one of the possible long term effects of COVID-19
  • The macromolecular crystallography beamlines at the Australian Synchrotron continue to provide insights into the structural biology of COVID-19 

The Macromolecular and microfocus beamlines at the Australian Synchrotron continue to be an invaluable resource for studies in structural biology relating to COVID-19.

This week researchers from La Trobe University reported that they have identified a key mechanism in how SARS-CoV-2 damages lung tissue.

Some patients report long term-COVID symptoms affecting their breathing for months after recovering from an initial COVID-19 infection.

Read more on ANSTO website

Structure-guided nanobodies block SARS-CoV-2 infection

Structure-guided nanobodies block SARS-CoV-2 infection

Monoclonal antibodies are valuable weapons in the battle against COVID-19 as direct-acting antiviral agents (1). Central to virus replication cycle, the SARS-CoV-2 spike protein binds the host cell receptor and engages in virus-host membrane fusion (2). Conformational flexibility of the spike protein allows each of its receptor binding domains (RBDs) to exist in two major configurations: a “down” conformation that is thought to be less accessible to binding of many neutralizing antibodies and an “up” conformation that binds both the receptor and neutralizing antibodies (3-5). Some neutralizing antibodies bind to the RBD in the “up” conformation and compete with the receptor (6, 7), while some neutralizing antibodies bind and stabilize the “down” confor­mation to prevent the conforma­tional changes required for viral entry, thereby hindering infection (8, 9).

Unfortunately, antibody molecules can be more difficult to produce in large quantities and are relatively costly to produce. Single domain antibodies, also known as nanobod­ies, offer an opportunity to rapidly produce antiviral agents for immun­ization and for therapy. Nanobodies are easier to produce, have high thermal stability and have the potential to be administered by inha­lation.

Read more on the SLAC website

Image: Bivalent nanobodies inducing post-fusion conformation of the SARS-CoV-2 spike protein: SARS-CoV-2 spike proteins are in a fusion inactive configuration when the RBDs are in the down conformation (left). Binding of bivalent nanobody (red and green ribbons joined by yellow tether) stabilizes the spike in an active conformation with all RBDs up (middle), triggering premature induction of the post-fusion conformation, which irreversibly inactivates the spike protein (right).

Combatting COVID-19 with crystallography and cryo-EM

Combatting COVID-19 with crystallography and cryo-EM

Crystallography and cryo-electron microscopy are vital tools in the fight against COVID-19, allowing researchers to reveal the molecular structures and functions of the SARS-CoV-2 virus, paving the way for new drugs and vaccines. Since the start of the pandemic, the ESRF has mobilised its crystallography and cryo-electron microscopy expertise and made its new Extremely Brilliant Source available as part of the collective effort to address this critical global health challenge.

When the WHO declared the outbreak of COVID-19 a public health emergency of international concern in early 2020, it signalled the start of a race against time for scientists to understand how the newly identified SARS-CoV-2 virus functioned and to develop treatments for the disease. Structural biologists around the world pitched in, determining the structures of most of the 28 proteins encoded by the novel coronavirus. This remarkable collective effort resulted in over a thousand 3D structural models of SARS-CoV-1 and SARS-CoV-2 proteins deposited in the Protein Data Bank (PDB) public archive in just one year [1]. Researchers and drug developers rely on these models to design antiviral drugs, therapies and vaccines. However, the speed and urgency with which the SARS-CoV-2 protein structures were solved means that errors could inevitably slip in, with potentially severe consequences for drug designers targeting certain parts of the virus’s structure. 

Enter the Coronavirus Structural Task Force, an international team of 25 structural biologists offering their time and expertise to fix errors in structural models of the virus’s proteins in order to give drug designers the best possible templates to work from. Gianluca Santoni, crystallography data scientist in the ESRF’s structural biology group, is part of the task force, whose work is detailed in an article recently published in Nature Structural & Molecular Biology [2]. “Every week, we check the PDB for any new protein structure related to SARS-CoV-2,” he explains. “We push structural biology tools and methods to the limit to get every last bit of information from the data, to evaluate the quality and improve the models where possible.” 

To read more visit the ESRF website

Image: The coronavirus research project ‘COVNSP3’ is based on the use of the ESRF’s cryo-electron microscope facility, led by Eaazhisai Kandiah (pictured)

Credit: ESRF/S. Cande.

Beaming in on Coronavirus details

Beaming in on Coronavirus details

User operation resumed at European XFEL end of March, and the first experiments to receive beamtime are those being carried out at the Single Particles, Clusters, and Biomolecules & Serial Femtosecond Crystallography (SPB/SFX) instrument. They will focus on getting deeper insights into the Coronavirus, and, if successful, can lead to a better understanding of the structure of key Coronavirus proteins. New information about the shapes of these proteins, which the virus needs to copy itself, will aid scientists in their quest to find ways to fight COVID.

“Three user collaborations have proposed experiments that will use two distinct approaches to study the Coronavirus. Two collaborations lead by scientists from DESY and Diamond Light Source will look at the structure and binding of ligands to the proteases of the Coronavirus,” says Adrian Mancuso, leading scientist at the SPB/SFX instrument. A ligand is a molecule that binds another specific molecule or atom. Some ligands deliver a signal during the binding process and can be thought of as signaling molecules, which interact with proteins in target cells called receptors. At the European XFEL, scientists can potentially observe the process of these ligands attaching to proteins at atomic resolution, however, first an ordered crystal of the relevant protein is required. “XFELs are uniquely positioned to watch how irreversible processes in proteins—such as binding of potential drug candidates—happen,” explains Mancuso.

Read more on the European XFEL website

Image: A shot from the control hutch showing one of the first COVID-related beamtimes at SPB/SFX

Credit: European XFEL

Massive fragment screen points way to new SARS-CoV-2 inhibitors

Massive fragment screen points way to new SARS-CoV-2 inhibitors

Experiment with 2533 fragments compounds generates chemical map to future antiviral agents 

New research published in Science Advances provides a template for how to develop directly-acting antivirals with novel modes of action, that would combat COVID-19 by suppressing the SARS-CoV-2 viral infection. The study focused on the macrodomain part of the Nsp3 gene product that SARS-CoV-2 uses to suppress the host cell’s natural antiviral response. This part of the virus’s machinery, also known as Mac1, is essential for its reproduction: previous studies have shown that viruses that lack it cannot replicate in human cells, suggesting that blocking it with a drug would have the same effect.  

The study involved a crystallographic fragment screen of the Nsp3 Mac1 protein by an open science collaboration between researchers from the University of Oxford, the XChem platform at Diamond, and researchers from the QCRG Structural Biology Consortium at the University of California San Francisco.  The international effort discovered 234 fragment compounds that directly bind to sites of interest on the surface of the protein, and map out chemical motifs and protein-compound interactions that researchers and pharmaceutical companies can draw on to design compounds that could be developed into antiviral drugs.  This work is thus foundational for preparing for future pandemics.   

Read more on the Diamond website

Image: Principal Beamline Scientist on I04-1, Frank von Delft

Credit: Diamond Light Source

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

Promising candidates identified for COVID drugs

Promising candidates identified for COVID drugs

A team of researchers has identified several candidates for drugs against the coronavirus SARS-CoV-2 at DESY´s high-brilliance X-ray lightsource PETRA III. They bind to an important protein of the virus and could thus be the basis for a drug against Covid-19.

In a so-called X-ray screening, the researchers, under the leadership of DESY, tested almost 6000 known active substances that already exist for the treatment of other diseases in a short amount of time. After measuring about 7000 samples, the team was able to identify a total of 37 substances that bind to the main protease (Mpro) of the SARS-CoV-2 virus, as the scientists report online today in the journal Science. Seven of these substances inhibit the activity of the protein and thus slow down the multiplication of the virus. Two of them do this so promisingly that they are currently under further investigation in preclinical studies. This drug screening – probably the largest of its kind – also revealed a new binding site on the main protease of the virus to which drugs can couple.

Read more on the DESY website

Image: In the control hutch of the PETRA III beamline P11, DESY researcher Wiebke Ewert shows on a so-called electron density map where a drug candidate (green) binds to the main protease of the corona virus (blue).

Credit: DESY, Christian Schmid

New targets for antibodies in the fight against SARS-CoV-2

New targets for antibodies in the fight against SARS-CoV-2

An international team of researchers examined the antibodies from a large cohort of COVID-19 patients. Due to the way antibodies are made, each person that is infected has the potential to produce many antibodies that target the virus in a slightly different way. Furthermore, different people produce a different set of antibodies, so that if we were to analyse the antibodies from many different patients, we would potentially be able to find many different ways to neutralise the virus.

The research article in the journal Cell is one of the most comprehensive studies of its kind so far. It is available online now and will be published in print on 15 April. These new results now show that there are many different opportunities to attack the virus using different antibodies over a much larger area than initially thought/mapped.

Professor Sir Dave Stuart, Life Sciences Director at Diamond and Joint head of Structural Biology at the University of Oxford, said:

SARS CoV-2 is the virus that causes COVID-19. Once infected with this virus, the human immune system begins to fight the virus by producing antibodies. The main target for these antibodies is the spike protein that protrudes from the virus’ spherical surface. The spike is the portion of the virus that interacts with receptors on human cells. This means that if it becomes obstructed by antibodies, then it is less likely that the virus can interact with human cells and cause infection.

By using Diamond Light Source, applying X-ray crystallography and cryo-EM, we were able to visualise and understand antibodies interact with and neutralize the virus. The study narrowed down the 377 antibodies that recognize the spike to focus mainly on 80 of them that bound to the receptor binding domain of the virus, which is where the virus spike docks with human cells.

Read more on the Diamond website

Image: Figure from the publication showing how the receptor binding domain resembles a human torso.

Credit: The authors (Cell DOI: 10.1016/j.cell.2021.02.032)

World Science Day spotlight: Collaborating to tackle SARS-CoV-2

World Science Day spotlight: Collaborating to tackle SARS-CoV-2

Science facilities worldwide have been working around the clock to drive forward SARS-CoV-2 research to alleviate the suffering that the COVID-19 pandemic is currently causing.

Today (November 10), in recognition of World Science Day for Peace and Development, the collective efforts of thousands of scientists and technical experts is being marked through this year’s focus – “Science for and with Society in dealing with the global pandemic.”

At the start of the pandemic, the facilities that make up the Lightsources.org collaboration were swift to ensure that rapid access was available for researchers working on SARS-CoV-2. This has led to a large body of research being undertaken at synchrotrons and free electron lasers.  The aims have been varied and include mapping the structure of the virus; finding binding sites for drugs to lock into; screening existing drugs to establish if they have a role to play in treating patients; understanding the impact of the virus on the lungs; and understanding the immune response so vaccines can be designed to illicit an immune response in the body.

A dedicated, regularly updated, web page – Lightsource research for SARS-CoV-2 – draws together all this research, along with other publications and resources.  It also includes links for researchers wishing to gain rapid access for their SARS-CoV-2 experiments.

The World Science Day for Peace and Development was created as a follow-up to the World Conference on Science, organised jointly by UNESCO and the International Council for Science in Budapest (Hungary) in 1999.

By linking science more closely with society, World Science Day for Peace and Development aims to ensure that citizens are kept informed of developments in science. It also underscores the role scientists play in broadening our understanding of the remarkable, fragile planet we call home and in making our societies more sustainable.

Learn more about World Science Day for Peace and Development on the UNESCO website

Image: World Science Day for Peace and Development 2020 poster

Credit: UNESCO

FIRST EXPERIMENTS ARE CARRIED OUT ON SIRIUS

FIRST EXPERIMENTS ARE CARRIED OUT ON SIRIUS

The new Brazilian synchrotron light source, Sirius, from the Brazilian Synchrotron Light Laboratory (LNLS) at the Brazilian Center for Research in Energy and Materials (CNPEM), carried out the first experiments on one of its beamlines this week. The first research station to start operating, still in the commissioning stage, can reveal details of the structure of biological molecules, such as viral proteins. These first experiments are part of an effort by CNPEM to provide a cutting-edge tool to the Brazilian scientific community working in SARS-CoV-2 research.

In these initial analyses, CNPEM researchers observed crystals of a coronavirus protein, essential for the development of COVID-19. The first results reveal details of the structure of this protein, important for understanding the biology of the virus and supporting research that seeks new drugs against the disease.

>Read more on the LNLS website