Exploring nature to treat multiple sclerosis
The chemical diversity in nature is unprecedented and exploring natural products for medical applications has a long tradition with many successful stories to be told. As a matter of fact, natural products or natural product-derived pharmaceuticals, constitute about half of all medical drugs on the market. One of the most well-known examples is the acetylsalicylic acid (Aspirin™), an anti-inflammatory compound originally derived (for the first time in 1828) from the bark of Salix trees. Another example is cyclosporine (Sandimmune™) an immunosuppressive peptide discovered at the beginnings of the 1970s and isolated from Slime moulds (Ascomycotas). The discovery of cyclosporine was revolutionary and is still used in the clinics today for the prevention of organ rejection following transplantation. These are just two examples of nature-derived products that found their way into clinical applications. Due to the broad distribution of natural products and thanks to the technological advances in chemical analytical tools to characterize and discover them, we will be hearing a lot more about these kinds of reports in the future (read also the Break: Fighting back antibiotic resistance: a new hope from the soil).
Multiple sclerosis is a chronic inflammatory autoimmune disease affecting approximately 2.5 million people worldwide. It affects the central nervous system and it arises when hyperproliferative immune cells induce destruction of the biological substance (myelin sheaths) around nerve fibres. As a consequence, communication within the nervous system degrades and leads to the clinical manifestation of the disease. Although several approaches and drugs are already on the market helping patients to cope with the symptoms, it remains an incurable disease. Furthermore, available drugs have to be administered intravenously with severe side-effects.
A new study led by a research team at the Medical University of Vienna alongside other international partners, highlights the potential application of circular plant peptides (cyclotides) in the treatment of multiple sclerosis. The team has demonstrated that following a plant-derived cyclotide oral treatment in a mouse model for multiple sclerosis, there is no progression of clinical disease symptoms. Importantly, this without inducing major adverse side-effects. Cyclotides are molecules present in very common plant families including coffee, violet flowers, grasses and plants of the nightshade family. They represent a large and diverse group of natural products which exhibit extraordinary stability and chemical properties, optimal prerequisites for oral drug development. Using this collection of nature-derived peptides in several pharmacological test systems, our experiments started by analysing the effects of cyclotide-enriched plant extracts of Oldenlandia affinis (coffee family) and Viola tricolor (violet family) towards certain immune cells (T-lymphocytes). We wanted to understand whether the cyclotides could modulate the proliferation of these cells. The proliferation capacity is essential for the immune system to fulfil its function against pathogenic invaders. However, when an autoimmune disease takes place, immune cells proliferation becomes hazardous due to its destructive potential against structures of the human body. Our results showed that certain cyclotides appear to be inhibiting this proliferation without inducing unwanted side-effects. Furthermore, detailed chemical analysis revealed that the natural occurring cyclotide kalata B1 (and later its synthetic analogue [T20K]kalata B1 - in short "T20K") acts as an active molecule to supress proliferation of immune cells. This led T20K to become a promising candidate for preclinical studies in the field of autoimmune diseases, especially multiple sclerosis.
Having said all of that, our discovery represents a possible breakthrough for the prevention of multiple sclerosis: a single dose of the peptide could prevent attacks and typical disease symptoms in animals. However, T20K is not yet a drug on the market available for clinical use. Hence, at present, there is no direct benefit for patients. Over the next years T20K needs to undergo rigorous clinical testing to confirm safety and efficacy in humans. In this direction, a recent licensing agreement signed by the Medical University of Vienna and the Medical Center - University of Freiburg, led to establish a company called Cyxone in 2015 (www.cyxone.com) aimed at developing novel cyclotide drugs for the treatment of autoimmune diseases. Cyxone's immediate focus is to bring T20K through a pre-clinical program required for clinical studies in multiple sclerosis. The main objective will be that of developing a safe and orally active drug. This is an exciting perspective as the Phase 1 clinical trial to develop a safe and orally active drug could begin as early as 2018.
Thell, K., Hellinger, R., Sahin, E., Michenthaler, P., Gold-Binder, M., Haider, T., Kuttke, M., Liutkevičiūtė, Z., Gransson, U., Gründemann, C., Schabbauer, G. and Gruber, C. (2016).Oral activity of a nature-derived cyclic peptide for the treatment of multiple sclerosis. Proceedings of the National Academy of Sciences, 113(15), pp.3960-3965.
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