A major challenge facing an ageing society is the burden of diseases with unmet medical needs such as neurological conditions including Parkinson’s, Alzheimer’s disease and multiple sclerosis but also cancer, diabetes, wound healing and inflammatory diseases. Addressing these needs requires radical new thinking to create innovative, cost-effective and safe solutions – one emerging possibility is the next generation of heparin and heparan sulfate (HS)-based therapeutics.
HS are highly sulfated polysaccharides found in animal tissues. HS binds a variety of protein ligands and regulates a range of biological activities, including development, angiogenesis, blood coagulation and tumor metastasis. Alterations in HS expression are associated with a multitude of diseases. By understanding their functions, we can unlock a tremendous potential for diverse biomedical applications. However, due to a fundamental technological bottleneck, it has been difficult to harness this potential.
HS-SEQ is a multi-interdisciplinary European consortium that will tackle this bottleneck by developing an integrated technology platform that can simultaneously record multiple molecular properties, such as molecular weight by mass spectrometry, collisional cross sections by ion mobility spectroscopy and vibrational properties by gas-phase infrared ion spectroscopy, and thus effectively sequence heparin/HS to determine the functional codes within. Implementation of the analytical platform requires a large collection of well-defined HS saccharides to generate reference databases that can patch molecular properties to structural features. This will be achieved in this program by implementing automated chemoenzymatic enzymatic synthesis of HS saccharides and fractionation protocols that can provide large collections of well-defined compounds. The collection of well-defined HS saccharides will also provide unique opportunities to develop an antibody toolkit to identify epitopes expressed by cells and tissues. Transformational applications of the new technologies will be pursued including the identification of HS codes that promote generation of dopaminergic neurons from pluripotent stem cells for cell replacement therapy in Parkinson’s disease and to achieve unprecedented in-depth analysis of pharmaceutical and next generation heparins.
