drugs – Lightsources.org

Tiny Chip-Based Device Performs Ultrafast Manipulation of X-Rays

2021/04/212021/04/22

Researchers from the U.S. Department of Energy’s Advanced Photon Source (APS) and Center for Nanoscale Materials at Argonne National Laboratory have developed and demonstrated new x-ray optics that can be used to harness extremely fast pulses in a package that is significantly smaller and lighter than conventional devices used to manipulate x-rays. The new optics are based on microscopic chip-based devices known as microelectromechanical systems (MEMS).

“Our new ultrafast optics-on-a-chip is poised to enable x-ray research and applications that could have a broad impact on understanding fast-evolving chemical, material and biological processes,” said research team leader Jin Wang from the X-ray Science Division Time Resolved Research (TRR) Group at the APS. “This could aid in the development of more efficient solar cells and batteries, advanced computer storage materials and devices, and more effective drugs for fighting diseases.”

In new results published in The Optical Society OSA) journal Optics Express, the researchers demonstrated their new x-ray optics-on-a-chip device (Fig. 1), which measures about 250 micrometers and weighs just 3 micrograms, using the TRR Group’s 7-ID-C x-ray beamline at the APS. The tiny device performed 100 to 1,000 times faster than conventional x-ray optics, which that tend to be bulky.

Read more on the APS website

Image: Fig. 1. The photograph shows two MEMS elements on a single chip (A), with the active elements of 250 µm × 250 µm, and the micrograph (B) highlighting the size of the diffractive element, as compared to a section of human hair (C).

New substance library to accelerate the search for active compounds

2020/07/132020/07/23

In order to accelerate the systematic development of drugs, the MX team at the Helmholtz-Zentrum Berlin (HZB) and the Drug Design Group at the University of Marburg have established a new substance library. It consists of 1103 organic molecules that could be used as building blocks for new drugs. The MX team has now validated this library in collaboration with the FragMAX group at MAX IV. The substance library of the HZB is available for research worldwide and also plays a role in the search for substances active against SARS-CoV-2.

For drugs to be effective, they usually have to dock to proteins in the organism. Like a key in a lock, part of the drug molecule must fit into recesses or cavities of the target protein. For several years now, the team of the Macromolecular Crystallography Department (MX) at HZB headed by Dr. Manfred Weiss together with the Drug Design Group headed by Prof. Gerhard Klebe (University of Marburg) has therefore been working on building up what are known as fragment libraries. These consist of small organic molecules (fragments) with which the functionally important cavities on the surface of proteins can be probed and mapped. Protein crystals are saturated with the fragments and then analysed using powerful X-ray light. This allows three-dimensional structural information to be obtained at levels of atomic resolution. Among other things, it is possible to find out how well a specific molecule fragment docks to the target protein. The development of these substance libraries took place as part of the joint Frag4Lead research project and was funded by the German Federal Ministry of Education and Research (BMBF).

Read more on the BESSY II website

Image : For the study, the enzyme endothiapepsin (grey) was combined with molecules from the fragment library. The analysis shows that numerous substances are able to dock to the enzyme (blue and orange molecules). Every substance found is a potential starting point for the development of larger molecules.

Credit: Wollenhaupt/HZB

A polymer coating makes Metal Organic Frameworks better at delivering drugs

2020/06/262020/07/14

Researchers use Synchrotron InfraRed microspectroscopy to study the dynamics of drug release from MOFs

How to efficiently deliver targeted, controlled and time-released doses of drugs is a significant challenge for biomedicine. Finding solutions to this challenge would result in substantial benefits for patients, including more effective drug therapy and fewer undesirable side effects. The porous nature of metal-organic frameworks (MOFs) makes them attractive candidates for drug-delivery systems as they can be tailored to hold and transport a variety of encapsulated guest molecules. To this end, employing MOFs as a drug delivery vehicle could offer potential solutions to accomplish the targeted and controlled release of anti-cancer drugs. However, understanding the precise chemical and physical transformations that MOFs undergo as these guest molecules are released is challenging. In work recently published in ACS Applied Materials & Interfaces, researchers from the University of Oxford, University of Turin, and Diamond Light Source used a combination of experimental and theoretical techniques to address this problem. They show how the combination of hydrophilic MOF-encapsulated drug with a hydrophobic polymeric matrix is a highly promising strategy to tune the drug release rate for optimal delivery. Their results demonstrate that high-resolution synchrotron InfraRed microspectroscopy is a powerful in situ technique for tracking the local chemical and physical transformations, revealing the dynamics underpinning the controlled release of drug molecules bound to the MOF pores.

Read more on Diamond Light Source website

Image: Using synchrotron infrared radiation to track the drug release process from MOF/Polymer composites.

Understanding how the taxanes antitumoral drugs modulate cell microtubules

2020/05/152020/05/20

Researchers have found that addition of paclitaxel (a type of antitumoral drug) to microtubules alters their structure. This compound modulates the material properties of microtubules by converting destabilized growing microtubule ends into regions resistant to depolymerisation, eventually leading to cell death. Results were obtained at the NCD beamline of the ALBA Synchrotron.

Paclitaxel, one of the most commonly used antitumoural drugs, modulates microtubules, the biopolymers responsible for many essential cellular functions including cell division, movement and intracellular transport. This kind of drugs target tubulin subunits, the main microtubule proteins, and interfere with their dynamics, which can have the effect of stopping a cell cycle and can lead to programmed cell death or apoptosis.

ALS reveals vulnerability in cancer-causing protein

2020/02/172020/02/20

A promising anticancer drug, AMG 510, was developed by Amgen with the help of novel structural insights gained from protein structures solved at the Advanced Light Source (ALS).

Mutations in a signaling protein, KRAS, are known to drive many human cancers. One specific KRAS mutation, KRAS(G12C), accounts for approximately 13% of non-small cell lung cancers, 3% to 5% of colorectal cancers, and 1% to 2% of numerous other solid tumors. Approximately 30,000 patients are diagnosed each year in the United States with KRAS(G12C)-driven cancers.

Despite their cancer-triggering significance, KRAS proteins have for decades resisted attempts to target their activity, leading many to regard these proteins as “undruggable.” Recently, however, a team led by researchers from Amgen identified a small molecule capable of inhibiting the activity of KRAS(G12C) and driving anti-tumor immunity. Protein crystallography studies at the ALS provided crucial information about the structural interactions between the potential drug molecule and KRAS(G12C).

Image: A structural map of KRAS(G12C), showing the AMG 510 molecule in the binding pocket. The yellow region depicts where AMG 510 covalently attaches to the KRAS protein.
Credit: Amgen

The mechanism of the most commonly used antimalarial drugs unveiled

2019/10/282019/11/01

For centuries, quinoline has been an effective compound in antimalarial drugs, although no one knew its mode of action in vivo.

Today, a team led by the Weizmann Institute has discovered its mechanism in infected red blood cells in near-native conditions, by using the ESRF, Alba Synchrotron and BESSY. They publish their results in PNAS.

Malaria remains one of the biggest killers in low-income countries. Estimates of the number of deaths each year range from 450,000 to 720,000, with the majority of deaths happening in Africa. In the last two decades, the malaria parasite has evolved into drug-resistant strains. “Recently, the increasing geographical spread of the species, as well as resistant strains has concerned the scientific community, and in order to improve antimalarial drugs we need to know how they work precisely”, explains Sergey Kapishnikov, from the University of Copenhagen, in Denmark, and the Weizmann Institute, in Israel, and leader of the study.

Plasmodium parasite, when infecting a human, invades a red blood cell, where it ingests hemoglobin to grow and multiply. Hemoglobin releases then iron-containing heme molecules, which are toxic to the parasite. However, these molecules crystallise into hemozoin, a disposal product formed from the digestion of blood by the parasite that makes the molecules inert. For the parasite to survive, the rate at which the heme molecules are liberated must be slower or the same as the rate of hemozoin crystallization. Otherwise there would be an accumulation of the toxic heme within the parasite.

>Read more on the ESRF website

Image (taken from BESSY II article): The image shows details such as the vacuole of the parasites (colored in blue and green) inside an infected blood cell.
Credit: S. Kapishnikov

Two other institutes, BESSY II at HZB and ALBA Synchrotron, have participated in this research. Please find here their published articles:

> X-ray microscopy at BESSY II reveal how antimalaria-drugs might work

> The mechanism of the most commonly used antimlalarial drugs in near- native conditions unveiled

Analyzing poppies to make better drugs

2019/09/112019/09/13

A team of researchers from the University of Calgary has uncovered new information about a class of plant enzymes that could have implications for the pharmaceutical industry. In a paper published in the Journal of Biological Chemistry, the scientists explain how they revealed molecular details of an enzyme class that is central to the synthesis of many widely used pharmaceuticals, including the painkillers codeine and morphine.

The team used the Canadian Light Source at the University of Saskatchewan and the SLAC National Accelerator Laboratory to better understand how the enzyme behaves, which is crucial for unleashing its potential to make novel medicines. “Until this study, we didn’t know the key structural details of the enzyme. We learned from the structure of the enzyme bound to the product how the methylation reaction locks the product into a certain stereochemistry. It was completely unknown how the enzyme did that before we determined this structure,” corresponding author Dr. Kenneth Ng explained.

Stereochemistry is an important concept when it comes to safety and efficacy in drug design. A molecule can have a few different arrangements—similar to how your left hand is a mirror image of your right hand. These arrangements can lead to very different effects.

Image: group photo of some of the researchers involved with this project. From left to right: Ken Ng (Professor and corresponding author), Jeremy Morris (PhD graduate and second author), Dean Lang (PhD student and first author), and Peter Facchini (Professor, CSO of Willow Biosciences and senior author).

A new generation of anti-malaria drugs

2019/09/052019/09/05

Malaria is endemic to large areas of Africa, Asia and South America and annually kills more than 400,000 people, a majority of whom are children under age 5, with hundreds of millions of new infections every year. Although artemisinin-based drug combinations are available to treat malaria, reports from Southeast Asia of treatment failures are raising concerns about drug resistance spreading to Africa. Fortunately, there is hope on the horizon because there are several new antimalarial drug candidates undergoing clinical testing as well as other promising drug targets that are under investigation.
An international research team has for the first time determined the atomic structure of a protein kinase called PKG in Plasmodium parasites that cause malaria—a finding that potentially will help create a new generation of anti-malarial drugs and advance fundamental research. PKG^[i] plays essential roles in the developmental stages of the parasite’s complex life cycle, so understanding its structure is key to developing malaria-fighting therapies that specifically target PKG and not other human enzymes, according to researcher Dr. Charles Calmettes.

Image: PKG crystal.

Preventing tumour metastasis

2019/08/222019/08/27

Researchers at the Paul Scherrer Institute, together with colleagues from the pharmaceutical company F. Hoffmann-La Roche AG, have taken an important step towards the development of an agent against the metastasis of certain cancers.

Using the Swiss Light Source, they deciphered the structure of a receptor that plays a crucial role in the migration of cancer cells. This makes it possible to identify agents that could prevent the spread of certain cancer cells via the body’s lymphatic system. The researchers have now published their results in the journal Cell.
When cancer cells spread in the body, secondary tumours, called metastases, can develop. These are responsible for around 90 percent of deaths in cancer patients. An important pathway for spreading the cancer cells is through the lymphatic system, which, like the system of blood vessels, runs through the entire body and connects lymph nodes to each other. In the migration of white blood cells through this system, for example to coordinate the defense against pathogens, one special membrane protein, the chemokine receptor 7 (CCR7) plays an important role. It sits in the shell of the cells, the cell membrane, in such a way that it can receive external signals and relay them to the interior. Within the framework of a joint project with the pharmaceutical company F. Hoffmann-La Roche AG (Roche), researchers at the Paul Scherrer Institute (PSI) have for the first time been able to decipher the structure of CCR7 and lay the foundation for the development of a drug that could prevent metastasis in certain prevalent cancer types, such as colorectal cancer.

Collaboration develops sensitive data protocol

2019/08/162019/08/22

MAX IV pairs up with Sprint Bioscience, a listed drug development company, in a new project to improve how companies can benefit from new, faster X-ray fragment screening experiments, while still protecting their valuable information during analysis at FragMAX.

Recently, the project was granted with 500 000 SEK from Sweden’s innovation agency Vinnova.
More or less, all pharmaceutical drugs are molecules binding to proteins in your body. When doing this, they either initiate or inhibit the process in which the target protein is involved. Proteins are in charge of everything from cells dividing at the right moment to the metabolism of the food you eat or signaling in the brain.

>Read more on the MAX IV website

Image: Sample holders
Credit: Ben Libberton

New approach for solving protein structures from tiny crystals

2019/05/032019/05/08

Technique opens door for studies of countless hard-to-crystallize proteins involved in health and disease

Using x-rays to reveal the atomic-scale 3-D structures of proteins has led to countless advances in understanding how these molecules work in bacteria, viruses, plants, and humans—and has guided the development of precision drugs to combat diseases such as cancer and AIDS. But many proteins can’t be grown into crystals large enough for their atomic arrangements to be deciphered. To tackle this challenge, scientists at the U.S. Department of Energy’s (DOE) Brookhaven National Laboratory and colleagues at Columbia University have developed a new approach for solving protein structures from tiny crystals.

The method relies on unique sample-handling, signal-extraction, and data-assembly approaches, and a beamline capable of focusing intense x-rays at Brookhaven’s National Synchrotron Light Source II (NSLS-II)—a DOE Office of Science user facility—to a millionth-of-a-meter spot, about one-fiftieth the width of a human hair.

Image: Wuxian Shi, Martin Fuchs, Sean McSweeney, Babak Andi, and Qun Liu at the FMX beamline at Brookhaven Lab’s National Synchrotron Light Source II, which was used to determine a protein structure from thousands of tiny crystals.

Researchers create the first maps of two melatonin receptors essential for sleep

2019/04/242019/05/03

A better understanding of how these receptors work could enable scientists to design better therapeutics for sleep disorders, cancer and Type 2 diabetes.

An international team of researchers used an X-ray laser at the Department of Energy’s SLAC National Accelerator Laboratory to create the first detailed maps of two melatonin receptors that tell our bodies when to go to sleep or wake up, and guide other biological processes. A better understanding of how they work could enable researchers to design better drugs to combat sleep disorders, cancer and Type 2 diabetes. Their findings were published in two papers today in Nature.

The team, led by the University of Southern California, used X-rays from SLAC’s Linac Coherent Light Source (LCLS) to map the receptors, MT1 and MT2, bound to four different compounds that activate them: an insomnia drug, a drug that mixes melatonin with the antidepressant serotonin, and two melatonin analogs.

>Read more on the LCLS at SLAC website

Image: The researchers showed that both melatonin receptors contain narrow channels embedded in the cell’s fatty membranes. These channels only allow melatonin, which can exist happily in both water and fat, to pass through, preventing serotonin, which has a similar structure but is only happy in watery environments, from binding to the receptor. They also uncovered how some much larger compounds only target MT1 despite the structural similarities between the two receptors.
Credit: Greg Stewart/SLAC National Accelerator Laboratory

A new study explains the inefficacy of some diabetes drugs

2019/04/162019/04/24

Synchrotron light has been used for the first time to simulate damages due to oxidative stress on the aldose reductase protein with the aim of obtaining its activated form.

This form of the protein, related with some several diabetic complications, is insensitive to the drugs being developed, which hinders the treatment. ALBA researchers have shown that chemical changes suffered by the protein under oxidative stress are the cause of drugs inefficacy in the attempt to block aldose reductase. The team of the Synchrotron suggests a new method for drugs design considering the changes in proteins under oxidative stress, like the ones involved in diseases such as cancer, Parkinson or Alzheimer.
The protein aldose reductase has been explored as a drug target since the 1980s for its implication in diabetic complications. Now, the team of the ALBA Synchrotron, in collaboration with the Autonomous University of Barcelona, has shown the reason why some drugs against the effects of diabetes under development do not work in the attempt to block aldose reductase.
This protein has mainly detoxifying functions inside the cell but it can also transform glucose into a molecule called sorbitol. Under hyperglycemic conditions (high level of glucose in blood), this reaction increases much more and sorbitol accumulates, consuming antioxidant defenses. So, if hyperglycemia situation becomes chronic – like in diabetes -, there are unbalanced conditions inside the cell that lead to harmful oxidative stress environment.

> Read more on the ALBA website

Image: Isidro Crespo, Judith Juanhuix and Albert Castellví, at the biolaboratoy of the ALBA Synchrotron.

Absorber captures excess chemotherapy drugs

2019/03/222019/04/10

The work opens up a new route to fighting cancer that minimizes drug toxicity and enables personalized, targeted, high-dose chemotherapy.

Most anticancer drugs are poisonous, so doctors walk a delicate line when administering chemotherapy. A dose must be sufficient to kill or stop the growth of cancer cells in the target organ, but not high enough to irreparably damage a patient’s other organs. To avoid this, doctors can thread catheters through the bloodstream to deliver chemotherapy drugs directly to the site of the tumor—a method known as intra-arterial chemotherapy. Still, typically more than half of the dose injected into the body escapes the target organ. Several years ago, researchers began working on a major improvement: placing a device “downstream” of the targeted organ to filter out excess chemo so that much less of the drug reaches the body as a whole.

>Read more on the Advanced Light Source

Image: (extract, see here the full image)
(a) Diagram of the proposed approach for drug capture using a 3D-printed cylindrical absorber. (b) Chemical structure of doxorubicin, the chemotherapy drug used in this study. (c) Schematic of the endovascular treatment of liver cancer. Excess drug molecules are captured by the absorber in the vein draining the organ. An introducer sheath guides the absorber to the desired location via a guide wire.

Clear view of “Robo” neuronal receptor opens door for new cancer drugs

2019/03/072019/03/12

During brain development, billions of neuron nerve cells must find accurate pathways in the brain in order to form trillions of neuronal circuits enabling us to enjoy cognitive, sensory and emotional wellbeing.

To achieve this remarkable precision, migrating neurons use special protein receptors that sense the environment around them and guide the way so these neurons stay on the right path. In a new study published in Cell, researchers from Bar-Ilan University and Tel Aviv University in Israel, EMBL Grenoble in France and University of Exeter in the UK report on their discovery of the intricate molecular mechanism that allows a key guidance receptor, “Robo”, to react to signals in its environment.

One of the most important protein signaling systems that guide neurons consists of the cell surface receptor “Robo” and its external guidance cue, “Slit”. “Slit and Robo can be identified in virtually all animals with a nervous system, from a 1 mm-long nematode all the way to humans,” explains researcher Yarden Opatowsky, associate professor and head of the Laboratory of Structural Biology at Bar-Ilan University and who led the research.

Image: A surface representation of the crystal structure of the extracellular portion of human Robo2. The yellow region represents the domain where dimerisation takes place. Here, we see it blocked by the other domains, meaning dimerisation cannot take place and that Robo2 is inactivated.
Credit: Y. Opatowsky.

Structural basis of neurosteroid anesthetic action on GABAA receptors

2019/02/282019/03/13

Type A γ-aminobutyric acid receptors (GABA_ARs) control neuronal excitability¹. They are targets for the treatment of neurological diseases and disorders and also for general anesthetics. The underlying mechanisms of these drugs’ action on GABA_ARs remain to be determined.
One of the mechanisms is to potentiate function of GABA_ARs via binding to the transmembrane domain (TMD)². Ample experimental evidence suggests that the TMD of GABA_ARs harbors sites for the primary actions of general anesthetics and neurosteroids. The TMD plays an essential role in functional transitions among the resting, activated, and desensitized states of these Cl^－-conducting channels.
Alphaxalone (5α-pregnan-3α-ol-11,20 dione) is a potent neurosteroid anesthetic. The anxiolytic, anticonvulsant, analgesic, and sedative-hypnotic effects of alphaxalone have been linked to its potentiation of GABA-evoked currents and direct activation of GABA_ARs³. However, the data about the alphaxalone binding site in GABA_ARs and the underlying structural basis of alphaxalone’s action are sparse.

Figure: Alphaxalone-induced structural changes at the bottom of the TMD (a) Bottom view of overlaid TM1-TM2 structures of the apo (orange) and alphaxalone-bound (cyan) α1GABA_AR chimera. (b) Side view of overlaid structures of apo (principal subunit – gold; complementary subunit – orange) and alphaxalone-bound (principal subunit – blue; complementary subunit – cyan) α1GABA_AR chimera. For clarity, only TM2 and TM3 are shown in the principal subunit and only TM1 and TM2 are shown in the complementary subunit. The arrow highlights structural perturbations originating from the alphaxalone binding site near W246 through the TM1-TM2 linker to the pore-lining residues P253 (-2′) and V257 (2′). (c) The 2F_O-F_C electron density maps (blue mesh, contoured at 1 σ) covering TM1-TM2 in the apo (left) and alphaxalone-bound (right) α1GABA_AR chimera. The sidechains are shown only for residues W246 to V257 (2′).