SARS-CoV-2 protein caught severing critical immunity pathway

Powerful X-rays from SLAC’s synchrotron reveal that our immune system’s primary wiring seems to be no match for a brutal SARS-CoV-2 protein.


Over the past two years, scientists have studied the SARS-CoV-2 virus in great detail, laying the foundation for developing COVID-19 vaccines and antiviral treatments. Now, for the first time, scientists at the Department of Energy’s SLAC National Accelerator Laboratory have seen one of the virus’s most critical interactions, which could help researchers develop more precise treatments.

The team caught the moment when a virus protein, called Mpro, cuts a protective protein, known as NEMO, in an infected person. Without NEMO, an immune system is slower to respond to increasing viral loads or new infections. Seeing how Mpro attacks NEMO at the molecular level could inspire new therapeutic approaches.

To see how Mpro cuts NEMO, researchers funneled powerful X-rays from SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL) onto crystallized samples of the protein complex. The X-rays struck the protein samples, revealing what Mpro looks like when it dismantles NEMO’s primary function of helping our immune system communicate.

“We saw that the virus protein cuts through NEMO as easily as sharp scissors through thin paper,” said co-senior author Soichi Wakatsuki, professor at SLAC and Stanford. “Imagine the bad things that happen when good proteins in our bodies start getting cut into pieces.”

The images from SSRL show the exact location of NEMO’s cut and provide the first structure of SARS-CoV-2 Mpro bound to a human protein.

“If you can block the sites where Mpro binds to NEMO, you can stop this cut from happening over and over,” SSRL lead scientist and co-author Irimpan Mathews said. “Stopping Mpro could slow down how fast the virus takes over a body. Solving the crystal structure revealed Mpro’s binding sites and was one of the first steps to stopping the protein.”

The research team from SLAC, DOE’s Oak Ridge National Laboratory, and other institutions published their results today in Nature Communications.

Read more on the SLAC website

Synchrotron light proves effectiveness of several drugs in virus infections like SARS-CoV2

Microtubules are intracellular structures that function as true cellular highways for the transport of substances, vesicles, organelles and even viruses, in the case that a cell gets infected. In most viral infections, they are the transport routes to generate the viral factories, regions close to the nucleus where virus production is concentrated.

The idea is to design drugs that, by binding to microtubules, prevent viruses from using them during the infection process. In general, drugs that target microtubules are called MTAs (microtubule targeting agents). There are two types: stabilizers (MSA) and destabilizers (MDA). Both are widely available and most of these drugs are in the WHO Essential Medicines List, and hence, they are therapeutic alternatives that are affordable and available worldwide.

Researchers from CIB Margarita Salas selected 16 commercially available MTA (including 15 in clinical use) to analyse their capacity to inhibit the viral replication against 5 different virus: the human common cold coronavirus (HCoV), the pandemic SARS-CoV-2 coronavirus, the vesicular stomatitis virus, the poxvirus vaccinia and African swine fever virus.

Scientist confirmed that the MTA tested had an effect on virus replication and spreading and that this effect varies according to the virus dependency on the microtubular network. “The inhibitory effect obtained varied depending on the specific functions that viruses have developed throughout evolution to exploit cellular transport machinery”, explains Dra. Marian Oliva, researcher at CIB Margarita Salas-CSIC.

In particular, the most complex use of microtubules filaments might correspond to coronavirus (CoVs), such as the one responsible for the Covid-19 pandemic. Microtubules are necessary both for virus internalization and later at several levels of the formation of the viral replication site. In fact, S and M coronavirus proteins (located on the virus surface) interact with tubulin (protein that forms microtubules) during the infection, although their specific function is currently unknown. Various projects involving the use of the ALBA Synchrotron are under way to study deeper these aspects.

Read more on the ALBA website

Image: Image obtained at the XALOC beamline of ALBA. Drug mebendazole (MBZ) bounds to the protein that forms the microtubules: tubulin (T2RT and T1D).

Structural studies of SARS-CoV-2 nucleocapsid protein

Perspectives in relation to diagnosis and drug design

 A novel zoonotic coronavirus SARS-CoV-2 was originally explored in Wuhan, China in December 2019 and further regarded to the serious pandemic known as COVID-19. In early March 2022, the global COVID-19 pandemic has caused over 453 million confirmed cases and over 6 million deaths (John Hopkins Coronavirus Resource Center,

 The COVID-19 virus and the emergence of new virus variants seriously threat to global public health. It is a strong requirement to develop the effective diagnostic tools which are able to quickly and reliably detect active SARS-CoV-2 infections.

 Structural proteins of the COVID-19 virus are very important to understand its pathogenic mechanism, thus leading to the development of antibodies, vaccines and drugs for targeting these proteins and viruses.

 SARS-CoV-2 comprised the four structural proteins; the spike (S), nucleocapsid (N), envelope (E) proteins and membrane glycoprotein (M). A complete virus particle (virion) is represented in Figure 1. Cryo-electron microscopy is one of the powerful tools to determine the overall structure of the S protein, thus presenting a unique crown or ‘corona’-like shape.

 Three viral proteins; the spike (S), envelope (E) and membrane (M) are embedded in the outer layer of the corona viral particle. The corona viruses protect themselves from the surrounding environment, then the ribonucleic acid (RNA) forms a stable packed in the lipid membrane. The nucleocapsid protein (nucleoprotein) is responsible for tightly wrap the RNA of viruses. However, the fatty membrane of SARS-CoV-2 is sensible to be destroyed by soap, detergent or surfactant.

 The nucleocapsid protein significantly involves in viral genomic RNA binding, thus protecting the coiled RNA as its genetic material inside the virus particle. Moreover, the N protein also plays an important role in the early stages of viral infection when the RNA genome is first released into the target host cell.

 X-ray crystal structures of the N-terminal (PDB entry 7CDZ) and C-terminal domains have been illustrated here (PDB entry 6WZO). Holo structure of N-terminal domain in complex with double strand RNA (PDB entry 7ACS) has been determined by Nuclear Magnetic Resonance Spectroscopy technique.

Read more on the Thai Synchrotron website

Image:  Three dimensional models of the SARS-CoV-2 virion and a schematic diagram of its four structural proteins. 

Credit: Figures were modified from coronavirusexplained     

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:

Crossing the border for understanding how life is assembled

Ana’s #LightSourceSelfie from the ALBA synchrotron in Spain

Ana Joaquina Pérez-Berná is a beamline scientist at the ALBA synchrotron near Barcelona in Spain.

As a biologist working on the soft X-ray cryo tomography beamline (MISTRAL), her role involves supporting the users with their experiments and also doing her own research. The beamline’s capabilities enable scientists to study down at the cellular level and the research covers a wide variety of diseases such as malaria, zika virus and SARS-CoV-2, along with treatments such as antivirals and chemotherapy. When describing her work, Ana says, “You are the first person who can enter the cell and see how it is inside, discover how the virus builds its bio-factories inside the cells, or discover how therapies work. Crossing that border for understanding how life is assembled, that is a privilege!”

Lightsource research on SARS-CoV-2

Coronaviruses are a family which includes the common cold, SARS, MERS and the current outbreak of the disease COVID-19, caused by the SARS-CoV-2 virus.
Several facilities of our collaboration have started research about SARS-CoV-2 virus or launched open calls for rapid access. This post will be updated regularly.

Publications on SARS-CoV-2 Rapid Access


Published articles

2021.12.09 Diamond Light Source (UK) article on their website: Trigger of rare blood clots with AstraZeneca and other COVID vaccines found by scientists

2021.11.06 APS at Argonne National Laboratory (USA) article on their website: Advanced Photon Source Helps Pfizer Create COVID-19 Antiviral Treatment

2021.11.04 ESRF (France) article on their website: EBS X-rays show lung vessels altered by COVID-19 (

2021.08.11 BESSY II at HZB (Germany) article on their website: HZB coordinates European collaboration to develop active agents against Corona – Helmholtz-Zentrum Berlin (HZB) (

2021.08.10 Canadian Light Source article on their website: Developing antiviral drugs to treat COVID-19 infections

2021.07.06 European XFEL (Germany) article on their website: XFEL: Insights into coronavirus proteins using small angle X-ray scattering

2021.06.21 Diamond Light Source (UK) article on their website: X-ray fluorescence imaging at Diamond helps find a way to improve accuracy of Lateral Flow Tests

2021.06.17 Australian Synchrotron (ANSTO) article on their website: Research finds possible key to long term COVID-19 symptoms

2021.05.11 Swiss Light Source at PSI (Switzerland) article on their website: How remdesivir works against the coronavirus

2021.05.28 SLAC (CA / USA) article from the Stanford Synchrotron Radiation Lightsource (SSRL): Structure-guided Nanobodies Block SARS-CoV-2 Infection | Stanford Synchrotron Radiation Lightsource

2021.05.21 ALS (USA) article on their website: Guiding Target Selection for COVID-19 Antibody Therapeutics

2021.05.21 ESRF (France) article on their website: Combatting COVID-19 with crystallography and cryo-EM (

2021.05.18 ALS (USA) article on their website: How X-Rays Could Make Reliable, Rapid COVID-19 Tests a Reality | Berkeley Lab (

2021.04.27 Canadian Light Source (Canada), video on their website Investigating the long-term health impacts of COVID-19 (

2021.04.22 Synchrotron Light Research Institute (Thailand), article on their website: SLRI Presented Innovations Against COVID-19 Outbreak to MHESI Minister on His Visit to a Field Hospital at SUT

2021.04.16 Diamond Light Source (UK) article on their website: Massive fragment screen points way to new SARS-CoV-2 inhibitors

2021.04.14 SLAC (CA / USA), article also with news about research at Stanford Synchrotron Radiation Lightsource (SSRL):Researchers search for clues to COVID-19 treatment with help from synchrotron X-rays

2021.04.07 Diamond Light Source (UK), article on their website: First images of cells exposed to COVID-19 vaccine – – Diamond Light Source

2021.04.05 ALS (CA/USA) blog post on Berkeley Lab Biosciences website: New COVID-19 Antibody Supersite Discovered

2021.04.02 PETRA III at DESY (Germany), article and animation on their website DESY X-ray lightsource identifies promising candidate for COVID drugs

2021.03.26 Diamond Light Source (UK), article on their website: New targets for antibodies in the fight against SARS-CoV-2

2021.02.23 Australian Light Source (ANSTO) Australia, article on their website: Progress on understanding what makes COVID-19 more infectious than SARS

2020.12.02 ESRF (France), article and video on their website: ESRF and UCL scientists awarded Chan Zuckerberg Initiative grant for human organ imaging project

2020.11.10 Diamond Light Source (UK), article and video on their website: From nought to sixty in six months… the unmasking of the virus behind COVID-19

2020.10.29 Canadian Light Source (Canada) video on their website: Studying how to damage the COVID-19 virus

2020.10.07 National Synchrotron Light Source II (NSLS-II) at Brookhaven Lab (NY / USA) article on their website: Steady Progress in the Battle Against COVID-19

2020.10.07 Diamond Light Source (UK), article on their website: Structural Biology identifies new information to accelerate structure-based drug design against COVID-19

2020.10.06 MAX IV (Sweden), article on their website: Tackling SARS CoV-2 viral genome replication machinery using X-rays

2020.08.31 SLAC (CA / USA), article also with news about research at Stanford Synchrotron Radiation Lightsource (SSRL): SARS-CoV-2 Spike Protein Targeted for Vaccine

2020.08.27 Diamond Light Source (UK), article on their website: Structural Biology reveals new target to neutralise COVID-19

2020.08.27 Canadian Light Source (Canada) video on their website: Developing more effective drugs

2020.08.25 Australian Synchrotron (ANSTO) (Australia) article on their website: More progress on understanding COVID-19

2020.08.24 DESY (Germany) article on their website: PETRA III provides new insights into COVID-19 lung tissue

2020.08.11 Australian Synchrotron (ANSTO) (Australia) article on their website: Unique immune system of the alpaca being used in COVID-19 research

2020.07.30 Swiss Light Source at PSI (Switzerland) article on their website: COVID-19 research: Anti-viral strategy with double effect

2020.07.29 National Synchrotron Light Source II (NSLS-II) at Brookhaven Lab (NY / USA) article on their website: Ready to join the fight against COVID-19.

2020.07.20 ALBA (Spain) article on their website: A research team from Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC) uses synchrotron light to study the possible effect of an antitumoral drug of clinical use over the viral cycle of SARS-CoV-2 coronavirus. 

2020.07.15 ALS (USA) article on their website: Antibody from SARS Survivor Neutralizes SARS-CoV-2

2020.07.14 Diamond Light Source (UK), article on their website: Engineered llama antibodies neutralise Covid-19 virus

2020.06.17 European XFEL (Germany) article on their website: Pulling Together: A collaborative research approach to study COVID-19

2020.06.15 European XFEL (Germany) article on their website: Open Science COVID19 analysis platform online

2020.06.09 APS at Argonne National Laboratory (USA) article on their website: Novel Coronavirus Research at the Advanced Photon Source

2020.05. Società Italiana di Fisica publishes an article about research done at Elettra Sincrotrone Trieste (Italy) and the Advanced Light Source (CA / USA): Accelerator facilities support COVID-19-related research

2020.05.27 Diamond Light Source (UK), new animation video demonstrating the work that has been done at Diamond’s XChem facilities.

2020.05.19 Advanced Light Source (CA / USA), article about their latest results: X-ray Experiments Zero in on COVID-19 Antibodies

2020.05.15 Swiss Light Source (Switzerland), article about their first MX results: First MX results of the priority COVID-19 call

2020.05.14 MAX VI (Sweden), article about their research: Tackling SARS CoV-2 viral genome replication machinery using X-rays

2020.05.14 CHESS (NY/USA), article: CHESS to restart in June for COVID-19 research

2020.05.14 the LEAPS initiative brings together many of our European members. The initative published this brochure: Research at LEAPS facilities fighting COVID-19

2020.05.12 Diamond Light Source (UK), article about their collaboration in a consortium: UK consortium launches COVID-19 Protein Portal to provide essential reagents for SARS-CoV-2 research

2020.05.11 Advanced Photon Source (IL/USA), article: Studying Elements from the SARS-CoV-2 Virus at the Bio-CAT Beamline

2020.05.07 European XFEL (Germany), article: European XFEL open for COVID-19 related research

2020.05.06 ESRF (France), article: World X-ray science facilities are contributing to overcoming COVID-19

2020.04.29. BESSY II at HZB (Germany), article: Corona research: Consortium of Berlin research and industry seeks active ingredients

2020.04.29. Swiss Light Source and SwissFEL at PSI (Switzerland), interview series on the PSI website: Research on Covid-19

2020.04.23. PETRA III at DESY (Germany), article: X-ray screening identifies potential candidates for corona drugs

2020.04.21. MAX IV (Sweden), article: BioMAX switches to remote operations in times of COVID-19

2020.04.16. SLAC (CA / USA), article also with news about research at Stanford Synchrotron Radiation Lightsource (SSRL): SLAC joins the global fight against COVID-19

2020.04.15 Berkeley National Lab (CA/ USA), article with a focus on the research at the Advanced Light Source (ALS):
Staff at Berkeley Lab’s X-Ray Facility Mobilize to Support COVID-19-Related Research

2020.04.07 Diamond Light Source (UK), article: Call for Chemists to contribute to the fight against COVID-19
Crowdfunding: COVID-19 Moonshot

2020.04.07. ANSTO’s Australian Synchrotron (Victoria), article: Aiding the global research effort on COVID-19

2020.04.06. National Synchrotron Light Source II (NSLS-II) at Brookhaven Lab (NY / USA), article: Brookhaven Lab Mobilizes Resources in Fight Against COVID-19

2020.04.02. BESSY II at HZB (Germany), article: Corona research: Two days of measuring operation to find the right key

2020.03.31 Diamond Light Source (UK), article: Jointly with Exscientia and Scripps Research, Diamond aims to accelerate the search for drugs to treat COVID-19

2020.03.27 Argonne National Laboratory with the Advanced Photon Source (APS) and other facilities on-site (IL / USA), article: Argonne’s researchers and facilities playing a key role in the fight against COVID-19

2020.03.27 ANSTO’s Australian Synchrotron (Victoria), article and video: Helping in the fight against COVID-19

2020.03.25 PETRA III at DESY (Germany), article: Research team will X-ray coronavirus proteins

2020.03.23 Diamond Light Source (UK) releases its first animation explaining: SARS-CoV-2 Mpro Single Crystal Crystallography

2020.03.25 CERN Courrier (Switzerland) article about synchrotron research on SARS-CoV-2, written by Tessa Charles (accelerator physicist at the University of Melbourne currently based at CERN, completed her PhD at the Australian Synchrotron): Synchrotrons on the coronavirus frontline

2020.03.19 BESSY II at Helmholtz-Zentrum Berlin (Germany), research publication: Coronavirus SARS-CoV2: BESSY II data accelerate drug development

2020.03.19 BESSY II at Helmholtz-Zentrum Berlin (Germany), technique explanation webpage: Protein crystallography at BESSY II: A mighty tool for the search of anti-viral agents

2020.03.16 Diamond Light Source (UK), article on their “Coronavirus Science” website: Main protease structure and XChem fragment screen

2020.03.12. Elettra Sincrotrone (Italy), article on their website: New project to fight the spread of Coronavirus has been approved

2020.03.05. Advanced Photon Source (IL / USA), article on their website: APS Coronavirus Research in the Media Spotlight

2020.03.05. Advanced Photon Source (IL / USA), research publication: “Crystal structure of Nsp15 endoribonuclease NendoU from SARS-CoV-2,” bioRXiv preprint  DOI: 10.1101/2020.03.02.968388, Article on their website (source: Northwestern University): New Coronavirus Protein Reveals Drug Target

Facility Covid-19 research pages

The Canadian Light Source (Canada) has created a specific page highlighting their COVID-19 research: COVID-19 research at the Canadian Light Source

BESSY II at HZB (Germany) has set up a page where it shows their contributions to the research on SARS-CoV-2 , see here

DESY (Germany) has launched a new page dedicated to Corona Research:

Diamond Light Source (UK) has created a specific website “Coronavirus Science” with platforms for various audiences: scientific community, general public and the media:

ELETTRA (Italy) has launched a new page dedicated to COVID-19 research:

The Photon Division of PSI (Switzerland) have collated many information linked to their institute on coronavirus-relevant research (recent publications, rapid access…):

ALBA (Spain) has set up a dedicated area on their website for information related to COVID-19 (rapid access, publications etc):

The ALS (CA/USA) has created a page listing all COVID-19 related research:

Rapid access

Scientists can apply for rapid access at following facilities (only member facilities of are referenced, the most recent published (or updated) call is mentioned first).

  • The National Synchrotron Light Source II (NSLS-II) in NY / USA is offering a streamlined and expedited rapid access proposal process for groups that require beam time for structural biology projects directly related to COVID-19. The Center for Biomolecular Structure team is supporting remote macromolecular crystallography experiments at Beamlines 17-ID-1 (AMX) and 17-ID-2 (FMX) in this research area. To submit a macromolecular crystallography proposal for COVID-19 related research, use the following form:
  • The Advanced Photon Source (APS) at Argonne National Laboratory in IL / USA  user program is operational to support:

·         Research on SARS-CoV-2 or other COVID-19-related research that addresses the current pandemic.

·         Critical, proprietary pharmaceutical research.

·         Mail-in/remote access work for any research involving low-risk samples and most medium-risk samples (as defined on the APS ESAF form).

·         Limited in situ research (set-up with one person, and ability to carry out majority of experiment safely remotely)

PETRA III at DESY in Germany offers also Fast Track Access for Corona-related research:

Australian Synchrotron at ANSTO makes its macromolecular crystallography beamlines available to structural biologists in response to the COVID-19 pandemic:

North American DOE lightsource facilities have created a platform to enable COVID-19 research. There you can find ressources and points of contact to request priority access:
Structural Biology Resources at DOE Light Sources

Elettra Sincrotrone Trieste in Italy opens to remote acces following beamlines: XRD1, XRD2, SISSI-BIO and MCX thanks to an CERIC-ERIC initiative:

The Advanced Light Source (ALS) at LBNL in California / USA has capabilities relevant to COVID-19 and researchers can apply through their RAPIDD mechanism:

ALBA Synchrotron in Spain offers a COVID-19 RAPID ACCESS on all beamlines:

SOLARIS Synchrotron in Poland gives acces to its Cryo Electron Microscope thanks to an CERIC-ERIC initiative:

Swiss Light Source and Swiss FEL at PSI in Switzerland offer priority access to combating COVID-19:

Diamond Light Source in the United Kingdom opened also a call for rapid access:

Image: Electron density at the active site of the SARS-CoV-2 protease, revealing a fragment bound
Credit: Diamond Light Source

APS helps Pfizer create Covid-19 antiviral treatment

Pharmaceutical company Pfizer has announced the results of clinical trials of its new oral antiviral treatment against COVID-19. The new drug candidate, Paxlovid, proved to be effective against the SARS-CoV-2 virus, which causes COVID-19, according to results released by Pfizer on Nov. 5.

Scientists at Pfizer created Paxlovid with the help of the ultrabright X-rays of the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science user facility at DOE’s Argonne National Laboratory.

“Today’s news is a real game-changer in the global efforts to halt the devastation of this pandemic,” said Albert Bourla, chairman and chief executive officer of Pfizer, in a company press release. ​“These data suggest that our oral antiviral candidate, if approved or authorized by regulatory authorities, has the potential to save patients’ lives, reduce the severity of COVID-19 infections and eliminate up to nine out of 10 hospitalizations.”

DOE invests in user facilities such as the APS for the benefit of the nation’s scientific community, and supports biological research as part of its energy mission. This research has been critical in the fight against COVID-19. The DOE national laboratories formed the National Virtual Biotechnology Laboratory (NVBL) consortium in 2020 to combat COVID-19 using capabilities developed for their DOE mission, and that consortium helps support research into antiviral treatments such as Paxlovid.

Work to determine the structure of the antiviral candidate was done at the Industrial Macromolecular Crystallography Association Collaborative Access Team (IMCA-CAT) beamline at the APS, operated by the Hauptman-Woodward Medical Research Institute (HWI) on behalf of a collaboration of pharmaceutical companies, of which Pfizer is a member.

As a member of IMCA-CAT, Pfizer routinely conducts drug development experiments at the APS, and the process of narrowing down and zeroing in on this drug candidate was performed over many months, according to Lisa Keefe, executive director of IMCA-CAT and vice president for advancing therapeutics and principal scientist at Hauptman-Woodward Medical Research Institute. IMCA-CAT, she said, delivers quality results in a timely manner, much faster than the home laboratories of the companies themselves can do.

Read more on the APS website

Image: The IMCA-CAT beamline at the Advanced Photon Source, where work was done to determine the structure of Pfizer’s new COVID-19 antiviral treatment candidate.

Credit: Lisa Keefe, IMCA-CAT/Hauptman-Woodward Medical Research Institute

Nanobodies against SARS-CoV-2

Göttingen researchers have developed nanobodies – a type of antibodies – that efficiently block the coronavirus SARS-CoV-2 and its new variants. Those nanobodies, which originate from alpacas inoculated with part of the SARS-CoV-2 virus spike protein – the receptor-binding domain that the virus deploys for invading host cells – could serve as a potent drug against COVID-19. The researchers used the X10SA crystallography beamline at the Swiss Light Source to characterize the interaction between the nanobodies and the coronavirus spikes at the molecular level.

Unlike antibodies, nanobodies can be produced on an industrial scale and at a low cost and therefore meet the global demand for COVID-19 therapeutics. The new nanobodies, which can bind and neutralize the virus up to 1000 times better than previously developed antibodies, are currently in preparation for clinical trials.

Read more on the PSI website

Image: The figure shows how two of the newly developed nanobodies (blue and magenta) bind to the receptor-binding domain (green) of the coronavirus spike protein (grey), thus preventing infection with SARS-CoV-2 and its variants.

Credit: Thomas Güttler / Max Planck Institute for Biophysical Chemistry

Developing antiviral drugs to treat COVID-19 infections

The rapid development of safe and effective vaccines has helped bring the pandemic under control. However, with the rise of variants and an uneven global distribution of vaccines, COVID-19 is a disease we will have to manage for some time.

Antiviral drugs that target the way the virus replicates may be the best option for treating outbreaks of COVID-19 in unvaccinated and under-vaccinated populations.

Using the Canadian Light Source (CLS) at the University of Saskatchewan, researchers from the University of Alberta (U of A) have isolated some promising inhibitors that could be used to treat COVID-19 infections. The scientists used the synchrotron remotely during the facility’s special COVID-19 call for proposals, an initiative created to support research to help fight the pandemic.

The team’s findings have been recently published in the European Journal of Medicinal Chemistry.

“With the help of the CLS, and the multiple teams here at the U of A, including the our lab and the Young lab in the Department of Biochemistry, Vederas lab in the Department of Chemistry, and Tyrrell team in Medical Microbiology and Immunology Department, we’ve been very efficient at developing a group of inhibitors that is very promising,” said Joanne Lemieux, a professor at the U of A.

Read more on the CLS website

Image: Michel Fodje, CLS Senior Scientist, using the CMCF beamline at the CLS, which was used for this project.

Credit: Canadian Light Source

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

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

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

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

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

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

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