Hitting the sweet spot: Sialic acid sugars for the treatment of immune diseases and other disorders?
In addition to DNA, proteins and lipids, sugar molecules are essential building blocks for every living cell. There are many different types of sugar molecules in a cell which are linked to one another forming chain or tree-like sugar structures called glycans. Glycans can mainly be found on the cell surface where they are attached to proteins (glycoproteins) or lipids (glycolipids). Cell surface glycans vary enormously in size and composition and show a dazzling diversity and complexity. In humans and other mammals, many glycans have in common that they are capped with one particular type of sugar – sialic acid (Fig. 1).
At the cell surface, sialic acids fulfill many important biological functions. One of them is the regulation of the immune system, a collection of specialized cells that protect us against pathogens and cancer. To properly full fill its task, the immune system has to be turned on and off at exactly the right time. Sialic acids contribute to this process by interacting with a family of sialic acid-binding receptors on immune cells called Siglecs. In general, the interaction of sialic acids with Siglecs – the sialic acid-Siglec axis – determines the threshold for immune activation and helps the immune system to return to an off state (Fig. 2). If this interaction is disturbed, for instance because of a defect in sialic acid expression, regulation of the immune system is out of balance. As result the immune system can start to attack our own body cells leading to autoimmune diseases. On the other hand, cancer cells make use of the sialic acid-Siglec axis to escape from recognition by the immune system and to become resistant against cancer immunotherapy. Cancer cells express high levels of sialic acids that enable them to interact with Siglecs on immune cells. This interaction appears to turn off immune cells that otherwise would destroy the cancer cells.
Siglecs are not exclusively expressed on immune cells, they can also be found on bone cells (osteoclasts) or neural cells (microglia cells) which are involved in bone or brain maintenance, respectively. Failures in sialic acid-Siglec interactions have been linked to bone disease (osteoporosis) and neurological diseases like Alzheimer’s disease. As many aspects regarding sialic acids and Siglecs are still poorly understood, it may be extremely rewarding to study the sialic acid-Siglec axis in health and disease in greater detail and to develop novel therapies that can modulate it.
Interestingly, sialic acid sugars can be chemically modified in a way that alters their binding to Siglec receptors. Different research groups have shown that alterations of the sialic acid sugar exist that enhance Siglec binding. For such modified sialic acid to be functional and effectively interact with Siglecs on immune cells, they are best presented in a way that resembles their natural expression in glycans at the cell surface.
Chemically modified sialic acids can be presented to Siglecs in different ways. For instance, they can be attached to nanoparticles that are much smaller than a cell or protein-like structures that integrate into the surface of living cells. Moreover, using a chemical trick, sialic acids on the cell surface can directly be modified to enhance their Siglec binding. In cell culture and mouse experiments, it has already been shown that autoimmunity and inflammation could be reduced by targeting Siglecs on immune cells with the chemically modified sialic acids. Further studies are needed to fully exploit the therapeutic potential of these chemically modified sialic acids.
In conclusion, the sialic acid-Siglec axis regulates important processes in our body and an imbalance herein can contribute to the onset of different diseases. In the future, chemically modified sialic acid sugars with altered Siglec binding characteristics could be applied to control the sialic acid-Siglec axis for the treatment of autoimmunity, cancer and other diseases.
Christian Büll1,3, Torben Heise2, Thomas J Boltje2 and Gosse J Adema1,3
1Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences,
Radboud University Medical Center, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands
2Cluster for Molecular Chemistry, Institute for Molecules and Materials,
Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
3New address from 01-01-2017: Department of Radiation Oncology,
Radiotherapy & OncoImmunology Laboratory,
Radboud Institute for Molecular Life Sciences, Radboud University Medical Center,
Geert Grooteplein Zuid 32, 6525 GA, Nijmegen, The Netherlands
Sialic Acid Mimetics to Target the Sialic Acid-Siglec Axis.
Büll C, Heise T, Adema GJ, Boltje TJ
Trends Biochem Sci. 2016 Jun