Biochimica et Biophysica Acta (BBA) - General Subjects
Review
Natural products: A continuing source of novel drug leads☆
Highlights
► We have given a history of natural products as drugs. ► We have discussed the reasons for the decreased interest in NPs in the Pharmaceutical industry. ► We have shown that the use of genomic techniques has allowed the recognition of new microbial sources of structures ► We demonstrate that the new frontier will be the interplay of genomics, chemistry and controlled biosynthesis. ► We demonstrate that biodiversity is in the microbial realm.
Introduction
Throughout the ages humans have relied on Nature to cater for their basic needs, not the least of which are medicines for the treatment of a wide spectrum of diseases. Plants, in particular, have formed the basis of sophisticated traditional medicine systems, with the earliest records, dating from around 2600 BCE, documenting the uses of approximately 1000 plant-derived substances in Mesopotamia. These include oils of Cedrus species (cedar) and Cupressus sempevirens (cypress), Glycyrrhiza glabra (licorice), Commiphora species (myrrh), and Papaver somniferum (poppy juice), all of which are still used today for the treatment of ailments ranging from coughs and colds to parasitic infections and inflammation. Egyptian medicine dates from about 2900 BCE, but the best known record is the "Ebers Papyrus" dating from 1500 BCE, documenting over 700 drugs, mostly of plant origin [1]. The Chinese Materia Medica has been extensively documented over the centuries [2], with the first record dating from about 1100 BCE (Wu Shi Er Bing Fang, containing 52 prescriptions), followed by works such as the Shennong Herbal (~ 100 BCE; 365 drugs) and the Tang Herbal (659 CE; 850 drugs). Likewise, documentation of the Indian Ayurvedic system dates from before 1000 BCE (Charaka; Sushruta and Samhitas with 341 and 516 drugs respectively) [3], [4].
The Greeks and Romans contributed substantially to the rational development of the use of herbal drugs in the ancient Western world. Dioscorides, a Greek physician (100 CE), accurately recorded the collection, storage, and use of medicinal herbs during his travels with Roman armies throughout the then "known world", whilst Galen (130–200 CE.), a practitioner and teacher of pharmacy and medicine in Rome, is well known for his complex prescriptions and formulae used in compounding drugs. The Arabs, however, preserved much of the Greco-Roman expertise during the Dark and Middle Ages (5th to 12th centuries), and expanded it to include the use of their own resources, together with Chinese and Indian herbs unknown to the Greco-Roman world. A comprehensive review of the history of medicine may be found on the website of the National Library of Medicine (NLM), United States National Institutes of Health (NIH), at www.nlm.nih.gov/hmd/medieval/arabic.html .
Section snippets
The Role of Traditional Medicine and Plants in Drug Discovery
Plant-based systems continue to play an essential role in healthcare, and their use by different cultures has been extensively documented [5], [6]. The World Health Organization (WHO) estimated in 1985 that approximately 65% of the population of the world predominately relied on plant-derived traditional medicines for their primary health care, while plant products also play an important, though more indirect role in the health care systems of the remaining population who mainly reside in
The Role of Marine Organisms in Drug Discovery
While marine organisms do not have a significant history of use in traditional medicine, the ancient Phoenicians employed a chemical secretion from marine molluscs to produce purple dyes for woolen cloth, and seaweeds have long been used to fertilize the soil. The world's oceans, covering more than 70% of the earth's surface, represent an enormous resource for the discovery of potential chemotherapeutic agents. Of the 33 animal phyla listed by Margulis and Schwartz [40] 32 are represented in
An Historical Perspective
The serendipitous discovery of penicillin from the filamentous fungus, Penicillium notatum, by Fleming in 1929, and the observation of the broad therapeutic use of this agent in the 1940s, ushered in a new era in medicine, "the Golden Age of Antibiotics", and promoted the intensive investigation of Nature as a source of novel bioactive agents [58]. Microorganisms are a prolific source of structurally diverse bioactive metabolites and have yielded some of the most important products of the
Other Sources
Teprotide, isolated from the venom of the pit viper, Bothrops jaracaca, led to the design and synthesis of the ACE inhibitors, captopril and enalapril (Fig. 10) [9], used in the treatment of cardiovascular disease, while epibatidine, isolated from the skin of the poisonous frog, Epipedobates tricolor, has led to the development of a novel class of potential painkillers (Fig. 10) [92]. A further notable discovery was the isolation of exendin-4 from the venom of the Gila monster, Heloderma
The Importance of Natural Products In Drug Discovery And Development
In 2 The Role of Traditional Medicine and Plants in Drug Discovery, 3 The Role of Marine Organisms in Drug Discovery, 4 The Role of Microorganisms in Drug Discovery., 5 Other Sources we have listed a relatively small number of selected examples of some of the useful drugs discovered from a variety of natural sources. In our paper published in 2012 [95], we analyzed the sources of new drugs over the period 01/1981-12/2010, and classified these compounds as N (an unmodified natural product), NB
Classical Natural Sources: Untapped Potential.
The exceptional complexity and molecular diversity of natural products has been highlighted in earlier sections, but even more remarkable is the fact that the surface of these unique natural resources has barely been scratched. Despite the intensive investigation of terrestrial flora, it is estimated that only 6% of the approximately 300,000 species (some estimates are as high as 500,000 species) of higher plants have been systematically investigated, pharmacologically, and only some 15%
The Unexplored Potential of Microbial Diversity.
Until recently, the inability to cultivate most naturally occurring microorganisms has severely limited the study of natural microbial ecosystems, and it has been estimated that much less than 1% of microorganisms seen microscopically have been cultivated. Yet, despite this limitation, the number of highly effective microbe-derived chemotherapeutic agents discovered and developed thus far has been impressive. Given the observation that “a handful of soil contain billions of microbial organisms”
Total Synthesis
The total synthesis of complex natural products has long posed challenges to the top synthetic chemistry groups worldwide, and has led to dramatic advances in the field of organic chemistry, particularly at the turn of the 21st Century and onwards [195]. As eloquently stated by Nicolaou and his coauthors in 2000: “Today, natural product total synthesis is associated with prudent and tasteful selection of challenging and preferably biologically important target molecules; the discovery and
The Rio Convention
In May of 1992, the Nairobi Conference led directly to the opening of what has become known as the Convention on Biodiversity (CBD) which was opened for signature at the Earth Summit in Rio, and by the end of the first year, it had been signed by 168 nations. The history can be found at the following URL: http://www.cbd.int/history/
Although the CBD was signed by the US President, it has never been ratified by the US Senate, so the USA is one of the very few nations that are not a voting member
Summary
The preceding sections have provided a very brief impression of the importance of natural products, both as pharmaceutical agents and/or as leads to bioactive molecules. With the emergence of novel screening systems related to the explosion of genetic information accelerating, the need to rapidly identify effective, novel lead structures is a vital necessity. We believe that a very significant portion of these leads will continue to be natural product derived. It should be remembered that
References (254)
- et al.
Epidemiology of drug-resistant malaria
Lancet Infect. Dis.
(2002) - et al.
Atermisinin: Discovery from the Chinese herbal garden
Cell
(2011) - et al.
Abraxane, a novel cremophor-free, albumin-bound particle form of paclitaxel for the treatment of advanced non-small-cell lung cancer
Ann. Oncol.
(2006) - et al.
The chemistry and biology of the maytansinoid antitumor agents
C. R. Chimie
(2008) Potent antibody drug conjugates for cancer therapy
Curr. Opin. Chem. Biol.
(2009)- et al.
Antibody-drug conjugates: Targeted drug delivery for cancer
Curr. Opin. Chem. Biol.
(2010) - et al.
Design of next-generation protein therapeutics
Curr. Opin. Chem. Biol.
(2010) - et al.
Lessons from the past and charting the future of marine natural products drug discovery and chemical biology
Chem. Biol.
(2012) - et al.
Cyclization of conotoxins to improve their biopharmaceutical properties
Toxicon
(2012) - et al.
Case history: Discovery of eribulin (halaven™), a halichondrin b analogue that prolongs overall survival in patients with metastatic breast cancer
Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (embrace): A phase 3 open-label randomised study
Lancet
A phase 2 study of patupilone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: Canadian urologic oncology group study p07a
Ann. Oncol.
The fungal cell wall as a drug target
Trends Microbiol.
Glucan synthase inhibitors as antifungal agents
Adv. Protein Chem.
Confronting the challenges of natural product-based antifungal discovery
Chem. Biol.
Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspecturn venom
J. Biol. Chem.
The beginnings of drug therapy: Ancient mesopotamian medicine
Drug News Perspect.
The pharmacology of chinese herbs
CRC handbook of ayurvedic medicinal plants
Ancient-modern concordance in ayurvedic plants: Some examples
Environ. Health Perspect.
Medicinal plants of native America
CRC ethnobotany desk reference
Medicinal plants in therapy
Bull. World Health Organ.
The value of plants used in traditional medicine for drug discovery
Environ. Health Perspect.
Natural products as leads for new pharmaceuticals
Isolation of artemisinin (qinghaosu) from artemisia annua growing in the United States
J. Nat. Prod.
Qinghaosu (artemisinin): An antimalarial drug from China
Science
A medicinal chemistry perspective on artemisinin and related endoperoxides
J. Med. Chem.
The molecular mechanism of action of artemisinin - the debate continues
Molecules
Artemisinin directly targets malarial mitochondria through its specific mitochondrial activation
PLoS One
Identification of an antimalarial synthetic trioxolane drug development candidate
Nature
Malaria-infected mice are cured by a single dose of novel artemisinin derivatives
J. Med. Chem.
Natural products and traditional medicine: Turning on a paradigm
J. Nat. Prod.
Plants used against cancer
Ethnobotany and drug discovery: The experience of the US National Cancer Institute
The vinca alkaloids
The vinca alkaloids
Podophyllotoxin and analogs
Podophyllotoxin and analogs
Taxol and its analogs
Taxol and its analogs
Taxol stabilizes microtubules in mouse fibroblast cells
Proc. Natl. Acad. Sci. U. S. A.
Taxoids: Cancer-fighting compounds from nature
Curr. Opin. Drug Discov. Dev.
Camptothecin and its analogs
Ansamitocins (maytansenoids)
Antibody-maytansinoid conjugates: A new strategy for the trreatment of cancer
Drugs Future
Trastuzumab emtansine: Tumor-activated prodrug (tap) immunoconjugate oncolytic
Drugs Future
Five kingdoms, an illustrated guide to the phyla of life on earth
Marine natural products
Nat. Prod. Rep.
Cited by (0)
- ☆
-
Note: This chapter reflects the opinions of the authors, not necessarily those of the US Government.