drug development – Lightsources.org

Funding for Diamond-II approved

2023/09/062023/09/06

The Department for Science, Innovation and Technology together with Wellcome, one of the world’s largest biomedical charities, today (Wednesday 6th September) announced approval for the innovative update and expansion programme to the UK’s national synchrotron, Diamond Light Source, at a total project cost of £519.4M. The investment will see 86% come from the UK Government and 14% from Wellcome, the same proportion that has funded Diamond from its beginning.

The full approval of the upgrade, Diamond-II, is part of a major investment drive in cutting-edge facilities to keep UK researchers and innovators at the forefront of discovery and help address global challenges.

Sir Adrian Smith, Chair of the Board of Diamond Light Source and President of the Royal Society comments:

We are delighted that the government and the Wellcome Trust have agreed this substantial investment in science infrastructure which will ensure the UK is at the forefront of world class science. This investment in Diamond-II will strengthen the UK’s global scientific leadership and confirms the UK’s commitment to building on the success Diamond has achieved so far.

Secretary of State for Science, Innovation and Technology, the Rt Hon Michelle Donelan MP, said:

Our national synchrotron may fly under the radar as we go about our daily lives, but it has been crucial to some of the most defining discoveries in recent history – from kickstarting Covid drug development that allowed us to protect millions of Britons to advancing treatment for HIV.

Our investment will ensure one of the most pioneering scientific facilities in the world continues to advance discoveries that transform our health and prosperity, while creating jobs, growing the UK economy and ensuring our country remains a scientific powerhouse.

The overall transformational Diamond-II upgrade will take several years of planning and implementation. This will include a “dark period” of 18 months during which there will be no synchrotron light for the user community, followed by a period to fully launch the new facility with three new flagship beamlines and major upgrades to many other beamlines.

Read more on the Diamond website

Image: Touring Diamond’s experimental hall during celebrations to mark the funding announcement for Diamond-II.
L to R: Dr Richard Walker, Technical Director and Senior Responsible Owner for Diamond-II, Beth Thompson MBE Chief Strategy Officer at Wellcome, Dr Adrian Mancuso, Diamond’s Physical Science Director, Prof Sir Dave Stuart, Diamond’s Life Sciences Director, Secretary of State for Science, Innovation and Technology, the Rt Hon Michelle Donelan MP, Sir Adrian Smith, Chair of the Board of Diamond, and Executive Chair of STFC Professor Mark Thomson.

Credit: Diamond Light Source

Newly identified protein could help fight cancer

2023/07/122023/08/15

Researchers from the University of British Columbia (UBC) have identified a new protein that helps an oral bacterium thrive in other locations around the body. The discovery could eventually lead to the development of new drugs that specifically target the protein.

“This bacterium is common in the mouths of humans and generally doesn’t cause disease in that location. However, it can travel through the bloodstream to other areas of the body, which leads to some pretty big health concerns,” says Dr. Kirsten Wolthers, Associate Professor of Biochemistry and Microbiology at UBC’s Okanagan Campus.

Most notably, this bacteria is prevalent in the tumors of colorectal cancer patients. The presence of the bacteria can contribute to tumor growth, spread of cancer to other sites in the body, and resistance to chemotherapy.

With the help of the CMCF beamline at the Canadian Light Source (CLS), located at the University of Saskatchewan, Wolthers and her colleagues determined that the new protein they identified enables the bacteria to take essential nutrients, such as iron, from our blood cells.

Read more on the CLS website

Image: Alexis Gauvin, inspecting a protein sample for particulate matter, using the glove box. Gauvin is a biochemistry student and a member of Dr. Kirsten Wolthers’s research group in the Department of Chemistry, University of British Columbia (Okanagan Campus).

Developing pain medication with fewer side effects

2021/11/302021/12/01

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.

APS helps Pfizer create Covid-19 antiviral treatment

2021/11/202021/11/24

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

Developing new drugs for superbugs like MRSA

2021/11/172021/11/18

The team is using bright beams at the Canadian Light Source (CLS) at the University of Saskatchewan to image how potential antibiotic-enhancing drugs interact with a molecule vital for building the cell wall of bacteria.

Staphylococcus aureus (the “SA” part of MRSA) has a thick protective cell wall that can make it difficult for some antibiotic drugs to attack it. That wall is an attractive target for drugs. If a therapeutic can weaken or break the wall, then the bacteria will die.

One protein that makes an attractive target for drugs is called UppS. It is involved in assembling part of the lipid scaffold on which the wall is built. Attacking UppS could weaken the wall and make the bacteria more susceptible to existing antibiotics, says Sean Workman, a postdoctoral researcher in the Department of Biology at the University of Regina.

“By slowing down the function of UppS we can make the bacteria more sensitive to other drugs,” he says.

Eric Brown, a professor in the Department of Biochemistry and Biomedical Sciences at McMaster University, went looking for drugs that could target the early steps in the creation of the cell wall and found clomiphene, an already-approved fertility drug that could interfere with UppS. He and his colleagues then used the same techniques to find several new molecules that could do the same thing, two of which – MAC-0547630 and JPD447 – seemed to be worth a closer look.

Read more on the CLS website

Image:UppS protein crystals used to obtain high resolution diffraction data.

Credit: Canadian Light Source

Nanobodies against SARS-CoV-2

2021/08/302021/09/16

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.

Developing antiviral drugs to treat COVID-19 infections

2021/08/102021/08/11

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

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

2021/03/262021/03/26

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)

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

2021/01/142021/01/18

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.

The African fly of death might also save lives

2020/12/022020/12/03

For the first time, an international team of scientists recreated in the lab the molecule that allows the tsetse fly to feed on blood. It’s a powerful yet small anticoagulant with a unique and strong binding to thrombin, the key enzyme of the coagulation pathway. X-ray diffraction measurements at two synchrotron facilities ––ALBA and ESRF–– were instrumental to understand the structure and the mechanism of action of this molecule, which suggests it is also a promising platform for designing improved anticoagulant drugs.

In the waiting rooms of health care facilities around the world, millions of patients take anticoagulants every day. These are life-saving drugs for the treatment of cardiovascular diseases, which now are also being explored for their benefits to patients with advanced symptoms of COVID-19.

And, as incredible as it may seem, the tsetse fly, responsible for the sleeping sickness disease in humans, is now on the spotlight in the efforts to develop more powerful and safer anticoagulants.

In a study co-authored by Bárbara Calisto, researcher at the ALBA Synchrotron, an international team of scientists has become the first to recreate in the lab the molecule that the tsetse fly uses to prevent coagulation when it bites to feed. These bites are also the entry channel for the parasite that causes sleeping sickness, a life-threatening disorder, if untreated. And the reason why the tsetse fly has been dubbed as the fly of death in Africa.

Read more on the ALBA website

Image: Bárbara Calisto at the XALOC beamline of the ALBA Synchrotron

Credit: ALBA

Scientists discover potential method to starve the bacteria that cause Tuberculosis

2020/11/252020/11/30

By deepening our understanding of how Tuberculosis bacteria feed themselves, University of Guelph researchers have identified a potential target for drug treatment. The team used the Canadian Light Source (CLS) at the University of Saskatchewan to image the bacteria in fine detail.

The infectious disease Tuberculosis (TB) is one of the leading causes of death worldwide. While rates of TB in Canada have remained relatively static since the 1980s, the disease disproportionately affects Indigenous populations. With TB-causing bacteria becoming increasingly resistant to antibiotics, researchers and drug makers are eager to find new, more effective treatments.

Researchers have known for some time that the bacteria that causes TB (Mycobacterium tuberculosis) uses our body’s cholesterol – a steroid – as a food source. Other relatives of the bacteria that do not cause disease share its ability to break down steroids. In this study, the University of Guelph team identified the structure of an enzyme (acyl CoA dehydrogenase) involved in steroid degradation in another member of the same bacteria family, called Thermomonospora curvata.

Read more on the CLS Website

Image: This rendering shows the shape of a tunnel (orange) where the substrate binds. Any drugs targeting this enzyme would need to fit to this pocket.

Visualising the bionanomachines that create potent antibiotics

2020/04/302020/05/05

… and other modern drugs.

Researchers from McGill University and Yale University used the Canadian Light Source (CLS) at the University of Saskatchewan to make a discovery that could help design future therapeutic drugs. The research team studied how mega-enzymes, known as nonribosomal peptide synthetases (NRPSs), create potent antibiotics, immunosuppressants and other modern drugs.

In a paper featured on the cover of the May 2020 issue of Nature Chemical Biology, the team reports how they were able to visualize an NRPSs’ mechanical system using the CMCF beamline at the CLS.

Image: Associate Professor Schmeing in the lab