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Discovery and resupply of pharmacologically active plant-derived natural products

Significance Statement

Natural products research on the rise

Natural products research on the rise Natural products yielded many successful medications in the past, but in the recent decades pharmaceutical industry shifted its focus on synthetic compounds as major source for development of new small molecule therapeutics. One of the important underlying reasons for this shift is the more difficult resupply of natural products, which are often not present in their natural sources in sufficient amounts to meet market needs, or have complex chemical structures hindering the development of economically viable total chemical synthesis approaches. Further difficulties are caused by the lower compatibility of natural products with established high throughput screening platforms, and patentability complications arising from the need to share patent rights with countries from which the natural product originates and from the general uncertainty existing in respect of patenting of unmodified natural products (resulting from the fundamental complexity of the question whether a natural material or phenomenon is patentable or not).

Paralleling the change of pharmaceutical industry focus, there has been a decline in the number of new drugs reaching the market in the recent years. Despite of being neglected, natural compounds have some important advantages as a pool for drug discovery, including high structural diversity, chemico-physical properties distinct from synthetic compounds, and sometimes the existence of prior hints for therapeutic effectiveness coming from use in traditional folk medicine. Reflecting better appreciation of advantages of natural products and the re-emerging scientific interest in medicinal plants-based natural product drug discovery, an increase in the number of scientific publications dealing with this research area is observed by publication trend analysis (http://dx.doi.org/10.1016/j.biotechadv.2015.08.001). Consequently, despite the recent neglecting by pharmaceutical industry, it appears very likely that natural products will remain an important source of new small molecule pharmaceuticals also in the future.

Reference: Atanasov AG, Waltenberger B, Pferschy-Wenzig EM, Linder T, Wawrosch C, Uhrin P, Temml V, Wang L, Schwaiger S, Heiss EH, Rollinger JM, Schuster D, Breuss JM, Bochkov V, Mihovilovic MD, Kopp B, Bauer R, Dirsch VM, Stuppner H. Discovery and resupply of pharmacologically active plant-derived natural products: A review. Biotechnol Adv. 2015 Aug 15. pii: S0734-9750(15)30027-6. http://dx.doi.org/10.1016/j.biotechadv.2015.08.001

About The Author

Dr. Atanas G. Atanasov is a research scientist and principle investigator at Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Austria. He has published over 50 peer-reviewed original research articles and reviews in the field of molecular medicine, mechanisms of pharmacological action, cell signaling, and regulatory mechanisms relevant for cardiometabolic disease and inflammation. Exploring innovative approaches for public research dissemination, he is also actively engaged in science communication in the social media.

Journal Reference

Biotechnology Advances, Available online 15 August 2015

Atanasov AG1, Waltenberger B2, Pferschy-Wenzig EM3, Linder T4, Wawrosch C5, Uhrin P6, Temml V7, Wang L5, Schwaiger S8, Heiss EH5, Rollinger JM9,Schuster D7, Breuss JM6, Bochkov V10, Mihovilovic MD4, Kopp B5, Bauer R11, Dirsch VM5, Stuppner H8.

Show Affiliations

1Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria. Electronic address: [email protected]

2Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria. Electronic address: [email protected]

3Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz, Universitätsplatz 4/I, 8010 Graz, Austria. Electronic address: [email protected]

4Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163-OC, 1060 Vienna, Austria.

5Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.

6Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.

7Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.

8Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.

9Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria; Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.

10Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Graz, Humboldtstrasse 46/III, 8010 Graz, Austria.

11Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz, Universitätsplatz 4/I, 8010 Graz, Austria.

Abstract

Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a “screening hit” through a “drug lead” to a “marketed drug” is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis.

While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future.

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Discovery resupply pharmacologically active plant-derived natural products - global medical discovery