Tag: drug

Picking up good vibrations – of proteins – at CHESS

Picking up good vibrations – of proteins – at CHESS

A new method for analyzing protein crystals – developed by Cornell researchers and given a funky two-part name – could open up applications for new drug discovery and other areas of biotechnology and biochemistry.

The development, outlined in a paper published March 3 in Nature Communications, provides researchers with the tools to interpret the once-discarded data from X-ray crystallography experiments – an essential method used to study the structures of proteins. This work, which builds on a study released in 2020, could lead to a better understanding of a protein’s movement, structure and overall function.

Protein crystallography produces bright spots, known as Bragg peaks, from the crystals, providing high-resolution information about the shape and structure of a protein. This process also captures blurry images – patterns and clouds related to the movement and vibrations of the proteins – hidden in the background of the Bragg peaks.

These background images are typically discarded, with priority given to the bright Bragg peak imagery that is more easily analyzed.

“We know that this pattern is related to the motion of the atoms of the protein, but we haven’t been able to use that information,” said lead author Steve Meisburger, Ph.D. ’14, a former postdoctoral researcher in the lab of Nozomi Ando, M.S. ’04, Ph.D. ’09, associate professor of chemistry and chemical biology in the College of Arts and Sciences. “The information is there, but we didn’t know how to use it.  Now we do.”

Meisburger worked closely with Ando to develop the robust workflow to decode the weak background signals from crystallography experiments called diffuse scattering. This allows researchers to analyze the total scattering from crystals, which depends on both the protein’s structure and the subtle blur of its movements.

Their two-part method – which the team dubbed GOODVIBES and DISCOBALL – simultaneously provides a high-resolution structure of the protein and information on its correlated atomic movements.

GOODVIBES analyzes the X-ray data by separating the movements – subtle vibrations – of the protein from other proteins that might be moving around it. DISCOBALL independently validates these movements for certain proteins directly from the data, allowing researchers to trust the results from GOODVIBES and understand what the protein might be doing.

Read more on CHESS website

Image: Meisburger, Case, & Ando (2020) Nat Commun 11, 1271

Undermining the foundations of bacterial resistance

Undermining the foundations of bacterial resistance

Scientists from the University of Guelph have used the Canadian Light Source (CLS) at the University of Saskatchewan to better understand how several infectious bacteria, including E. coli., build a protective sugar-based barrier that helps cloak their cells.

Published in the Journal of Biological Chemistry, the Guelph research provides the very early steps toward new treatments for E. coli and a whole range of bacteria. Their particular focus is on strains of E. coli that cause urinary tract and bloodstream infections, particularly those that are antibiotic resistant.

The research is looking to understand the enzyme that many infectious bacteria use to build the foundations of their protective capsule. The capsule helps shield the bacterium from attack by the human immune system and exists in many clinically distinct variants.

Making vaccines or drugs that targets the capsule itself directly is impractical as such treatments would target only a few bacteria. Instead, the Guelph team is focused on a key enzyme that builds the capsule foundation. This foundation could serve as a common point of attack, allowing a single treatment for several key pathogens infecting humans and livestock.

“We are interested in the machinery that builds the bacterium’s protective layer,” said Dr. Chris Whitfield, Professor Emeritus in the Department of Molecular and Cellular Biology. “By understanding and targeting the machinery, we can render the pathogen unable to survive in the host”.

Read more on the Canadian Light Source website

Image : Matthew Kimber, Chris Whitfield, and enzyme

Using light to switch drugs on and off

Using light to switch drugs on and off

Scientists at the Paul Scherrer Institute PSI have used the Swiss X-ray free-electron laser SwissFEL and the Swiss Light Source SLS to make a film that could give a decisive boost to developing a new type of drug. They made the advance in the field of so-called photopharmacology, a discipline that develops active substances which can be specifically activated or deactivated with the help of light. The study is being published today in the journal Nature Communications.

Photopharmacology is a new field of medicine that is predicted to have a great future. It could help to treat diseases such as cancer even more effectively than before. Photopharmacological drugs are fitted with a molecular photoswitch. The substance is activated by a pulse of light, but only once it has reached the region of the body where it is meant to act. And after it has done its job, it can be switched off again by another pulse of light.

This could limit potential side effects and reduce the development of drug resistance – to antibiotics, for example.

Licht-switchable drugs

To make conventional drugs sensitive to light, a switch is built into them. In their study, the scientists led by the principal authors Maximilian Wranik and Jörg Standfuss used the active molecule combretastatin A-4, which is currently being tested in clinical trials as an anti-cancer drug. It binds to a protein called tubulin, which forms the microtubules that make up the basic structure of the cells in the body, and also drive cell division. Combretastatin A-4, or “CA4” for short, destabilises these microtubules, thereby curbing the uncontrolled division of cancer cells, i.e. it slows down the growth of tumours.

In the modified CA4 molecule, a bridge consisting of two nitrogen atoms is added, which makes it particularly photoactive. In the inactive state, the so-called azo bridge stretches the molecular components to which it is attached to form an elongated chain. The pulse of light bends the bond, bringing the ends of the chain closer together – like a muscle contracting to bend a joint. Crucially, in its elongated form, the molecule does not fit inside the binding pockets of the tubulin – depressions on the surface of the protein where the molecule can dock in order to exert its effect. However, when the molecule is bent, it fits perfectly – like a key in a lock. Molecules like this, which fit into corresponding binding pockets, are also called ligands.

Read more on the PSI website

Image: Jörg Standfuss (left) and Maximilian Wranik in front of the experimental station Alvra of the Swiss X-ray free-electron laser SwissFEL, where the photopharmacological studies were carried out. In the long term, the aim is to develop drugs that can be switched on and off by light.

Credit: Paul Scherrer Institute/Markus Fischer