Could more sugar-based drugs be on the way?

By Samantha Black, PhD, The Science Advisory Board editor in chief

March 20, 2020 -- Researchers from Denmark have developed a new technique to characterize complex sugar molecules in exquisite detail never before achieved, according to a report published on March 20 in Nature Communications. They hope to leverage the new structural information for the development of therapies.

Sugars such as polysaccharides are an essential component of many biological processes. Glycosaminoglycans (GAGs) are linear sulfated polysaccharides, some of the most negatively charged biopolymers in nature, and are commonly found on cell surfaces and in the extracellular matrix. Heparan sulfate (HS), a class of GAGs, orchestrate many biological processes, including cell migration, inflammation, anticoagulation, angiogenesis, and tumor metastasis. In fact, heparin, an ATIII-binding pentasaccharide, is currently one of the most used drugs to prevent coagulation.

However, little structural information is known about HS motifs due to technical limitations. Less than 20 larger oligosaccharide structures have ever been fully sequenced, even by advanced methodologies like nuclear magnetic resonance, chemical modification, or enzymatic deconvolution. Structural analysis of these compounds is limited to compositional analysis for disaccharide components obtained after exhaustive enzymatic digestions. This does not provide insight into larger bioactive motifs of HS chains, which are largely heterogenous.

"Determining the structures is a key question in the research about sugars," said lead author Rebecca L. Miller, PhD, assistant professor at the Copenhagen Center for Glycomics, in a statement. "If we know the structure, we can determine what the cues are for specific biological functions and consider potential ways to exploit this in the development of therapeutics. This is hugely important and clinically relevant, as shown by the widely used anticoagulant heparins, and the potential application of new heparin-based drugs for multiple diseases in the future."

Researchers would like to gain a deeper understanding of heparan sulfate structure-function relationships to potentially develop new HS-based therapies. Ion mobility mass spectrometry (IMMS) of glycans has previously demonstrated the ability to characterize not only the isomeric arrangements of glycan building blocks but also connectivity and configuration properties. Therefore, the researchers developed a new technique called shotgun ion mobility mass spectrometry sequencing (SIMMS2) that can obtain information about small fragments with limited digestion and reconstruct overlapping fragments to further characterize bioactive motifs.

From the analysis, the researchers were able to demonstrate that complete characterization of HS sequences could help decipher cues for fibroblast growth factor (FGF1/FGF2) bioactivation. They identified several hexasaccharide inhibitors that blocked FGF2 activation and another nine-base-pair compound that partially activated FGF2. These compounds could support the development of FGF-specific regulatory compounds for future use.

The research team at Copenhagen Center of Glycomics recently reported the first cell-based method (GAGOme) to produce all variants of GAGs for discovery of functions and development of therapeutics. They hope to combine the method with the new sequencing technique to understand the effects of heparins in cancer and neurogenerative diseases and pioneer new GAG therapeutics. The team has been awarded a European Union grant to understand heparan sulfate structural cues that regulate stem cells to generate specialized neurons for treatment of Parkinson's disease.

"The instrumentation behind this new method was invented by the company Waters Ltd in 2006 and is available to many pharmaceutical companies and researchers," said co-author Jeremy Turnbull, a professor at the University of Liverpool and Copenhagen Center for Glycomics, in the statement. "This means that the method could be easily implemented and widely used for drug discovery by many research groups in a short period of time."


Do you have a unique perspective on your research related to molecular biology? Contact the editor today to learn more.

---



A discovery of fungi – helping researchers identify new drugs
To address the need to identify new therapeutic targets, researchers at the Hubrecht Institute turned to fungi. The researchers tested secondary metabolites...
Waters installs first cyclic IMS mass spectrometer
On November 7, Waters Corporation announced that it installed the first-ever Waters Select Series Cyclic IMS (ion mobility spectrometry) mass spectrometer....

Copyright © 2020 scienceboard.net


Register below for our weekly Letter from the Editor to receive the latest Science news and insights.
Email
Conferences
Festival of Genomics & Biodata
January 28-29, 2021
London, Greater London United Kingdom
Lab of the Future USA
May 11-12, 2021
Boston, Massachusetts United States
Connect
Science Advisory Board on LinkedIn
Science Advisory Board on Facebook
Science Advisory Board on Twitter