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!”

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

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