Scientists have found a way to create artificial sugars that could lead to better ways to diagnose and treat diseases more accurately than ever before.
Sugars play a crucial role in human health and disease, far beyond being just an energy source. Complex sugars called glycans coat all our cells and are essential for healthy function. However, these sugars are often hijacked by pathogens such as influenza, Covid-19, and cholera to infect us.
One big problem in treating and diagnosing diseases and infections is that the same glycan can bind to many different proteins, making it hard to understand exactly what's happening in the body and has made it difficult to develop precise medical tests and treatments.
In a breakthrough, published in the journal Nature Communications, a collaboration of academic and industry experts in Europe, including from The University of Manchester and the University of Leeds, have found a way to create unnatural sugars that could block the pathogens.
The finding offers a promising avenue to new drugs and could also open doors in diagnostics by 'capturing' the pathogens or their toxins.
Professor Matthew Gibson, a researcher from Manchester Institute of Biotechnology at The University of Manchester, said "During the Covid-19 pandemic, our team introduced the first lateral flow tests which used sugars instead of antibodies as the 'recognition unit'. But the limit is always how specific and selective these are due to the promiscuity of natural sugars. We can now integrate these fluoro-sugars into our biosensing platforms with the aim of having cheap, rapid, and thermally stable diagnostics suitable for low resource environments."
Professor Bruce Turnbull, a lead author of the paper from the School of Chemistry and Astbury Centre for Structural Molecular Biology at The University of Leeds, said "Glycans that are really important for our immune systems, and other biological processes that keep us healthy, are also exploited by viruses and toxins to get into our cells. Our work is allowing us to understand how proteins from humans and pathogens have different ways of interacting with the same glycan. This will help us make diagnostics and drugs that can distinguish between human and pathogen proteins."
The researchers used a combination of enzymes and chemical synthesis to edit the structure of 150 sugars by adding fluorine atoms. Fluorine is very small meaning that the sugars keep their same 3D shape, but the fluorines interfere with how proteins bind them.
Professor Sabine Flitsch, a researcher from Manchester Institute of Biotechnology at The University of Manchester, said "One of the key technologies used in this work is biocatalysis, which uses enzymes to produce the very complex and diverse sugars needed for the library. Biocatalysis dramatically speeds up the synthetic effort required and is a much more green and sustainable method for producing the fluorinated probes that are required."
They found that some of the sugars they prepared could be used to detect the cholera toxin - a harmful protein produced by bacteria - meaning they could be used in simple, low-cost tests, similar to lateral flow tests, widely used for pregnancy testing and during the COVID-19 pandemic.
Dr Kristian Hollie, who led production of the fluoro-sugar library at the University of Leeds, said: "We used enzymes to rapidly assemble fluoro-sugar building blocks to make 150 different versions of a biologically important glycan. We were surprised to find how well natural enzymes work with these chemically modified sugars, which makes it a really effective strategy for discovering molecules that can bind selectively."
The study provides evidence that the artificial "fluoro-sugars" can be used to fine-tune pathogen or biomarker recognition or even to discover new drugs. They also offer an alternative to antibodies in low-cost diagnostics, which do not require animal tests to discover and are heat stable.
The research team included researchers from eight different universities, including Manchester, Imperial College London, Leeds, Warwick, Southampton, York, Bristol, and Ghent University in Belgium.
