Sclerostin inhibitors: NMR fighting osteoporosis

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  • Published: Sep 15, 2016
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Sclerostin inhibitors: NMR fighting osteoporosis

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Model of a Sclerostin-fragment (green) bound to the antibody AbD09097 (heavy and light chain in cyan and red, respectively; surface representation in grey). Credit: Thomas Mueller

Drugs that act as inhibitors of the protein sclerostin could be used to treat the debilitating bone-loss disease osteoporosis, according to researchers in Germany who used nuclear magnetic resonance (NMR) spectroscopy in their investigations.

Osteoporosis is a particularly debilitating disease that can affect anyone but is commonly presented in elderly women for whom a broken bone, hip, wrist, back, is often the first obvious symptom. It is essentially characterised by a weakening of the bones to a density 2.5 standard deviations below that of a young adult, as measured by dual-energy X-ray absorptiometry at the hip. Weaker bones are more liable to breaking and given that other illnesses affecting gait and balance can be present in the elderly it is a significant risk factor for morbidity and ultimately mortality where subsequent complications or infection arise.

Young people, especially women are encouraged to ingest plenty of calcium as a way of preventing the onset of osteoporosis and load-bearing exercise to boost bone density in youth and middle age are encouraged, However, the underlying causes are not clear and many other factors such as alcoholism, anorexia, hyperthyroidism, surgical removal of the ovaries, and kidney disease can play a role in the development of the condition. Moreover, various medications including certain anti-seizure medications, chemotherapy agents, proton pump inhibitors, selective serotonin reuptake inhibitors and steroids can all lead to worrying loss of bone density as people get older. Smoking and a lack of exercise are also risk factors for osteoporosis, as well as many other medical conditions, of course.

Neutralizing sclerostin

The protein, sclerostin, has been identified as an important target in the hunt for novel treatments for the disease. Sclerostin is made by bone cells, osteocytes and plays an important role in bone metabolism, acting as an anti-anabolic factor. If its normal activity is hindered in some way, the re-absorption of bone is reduced and bone re-growth triggered. As such, inhibitors of sclerostin are keenly sought as possible drugs for reducing this resorption and stimulating bone growth. Antibodies, as biological, as opposed to small-molecule, drugs are being developed with this in mind. Promising work by one company, for instance, suggests that inhibitory antibodies can lead to a bone mass increase in people suffering from osteoporosis.

Verena Boschert working for Thomas Müller at the Julius-von-Sachs Institute (Julius-Maximilians-Universität Würzburg, JMU, in Bavaria, Germany) is investigating sclerostin in collaboration with several project partners funded by the European Union and the Deutsche Forschungsgemeinschaft. They have produced ten new and promising sclerostin-inhibiting antibodies for testing. Now, they have crystallized the most likely of the candidate antibodies, AbD09097, and analysed its mode of action in detail and published details recently in the journal. Open Biology. "Our findings could have a positive impact on the design of new inhibitory antibodies targeting Sclerostin," suggests Boschert. The Würzburg team is working with AbD-Serotec's German subsidiary in Puchheim and demonstrated that AbD09097 could neutralize sclerostin.

Working on interactions

Additional work with Pepscan (Lelystad, The Netherlands) and the Leibniz Institute for Pharmacology in Berlin, Germany, allowed them to obtain an in-depth analysis of the binding epitopes using peptide chemistry and NMR spectroscopy. This ultimately revealed the binding site of the antibody in sclerostin the crucial centre for targeting the protein with small molecule drugs that would be easier and less costly to manufacture and develop than antibodies.

"Until now, we could only determine the structure of the antibody alone," Boschert explains. The next step will be to crystallize the antibody bound to Sclerostin or a binding fragment and so obtain an even more detailed view of the interaction.

Related Links

Open Biol 2016, 6, 160120: "The sclerostin-neutralizing antibody AbD09097 recognizes an epitope adjacent to sclerostin's binding site for the Wnt co-receptor LRP6"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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