Neglected Disease Pipeline > Targets > Natural
products
Background
Overview | Existing Products | Get Involved
What are Natural Products?
Natural products are organic molecules isolated from animals, plants, or microbes that can be used to treat human disease.
Overview
Through evolutionary pressure, nature has guided the production of an immense diversity of organic molecules for a variety of
biological purposes. In order to search natural sources for new therapeutics, generally crude fractions of biological material (often
plants, marine life, or soil microbes that cannot be cultured) are screened for biological activity. Fractions with activity are further
purified and retested until the bioactive natural product is identified.
Natural products are the cornerstone of modern therapeutics. Building on the discovery of morphine from poppy seeds in the 1800s
and penicillin from mold in the 1920s, natural products have been a key source of new therapeutics. Natural products are currently
used to treat cancer, high levels of cholesterol, fungal infections, bacterial infections, and parasitic diseases. As of 1990, nearly 80% of
all drugs in use were natural products or natural product derivatives.1
Despite the success of natural products as therapeutics, drug discovery for natural products faces many challenges:2
• Working with biological materials, many of which must be collected rather than laboratory raised, is inherently variable. The level
of an active product in an organism may vary with that organism’s life cycle or environmental conditions, which can lead to
variability in materials.
• Crude fractionations of biological materials are not as amenable to high throughput screening as highly pure fully synthetic
chemical libraries.
• Crude fractions used for screening are generally mixtures of hundreds of components, which can be quite challenging to fully
purify and identify.
• Natural products, once identified, are often complex molecules that are challenging and/or expensive to produce synthetically.
The number of natural product drug discovery programs has steadily declined since the 1980s, primarily because pharmaceutical
companies have shifted to using synthetic chemical libraries that are more amenable to high throughput screening and simplified
synthesis. Between 1981 and 2002, approximately 50% of all new chemical entities approved by the U.S. Food & Drug Administration
(FDA) were natural products, natural product derivatives, or synthetic mimetics related to natural products.2,3 However, clinical trials for
new natural product therapeutics dropped 30% between 2001 and 2008.1
Despite this shift, natural products remain an important part of the drug discovery process. They are often used as a starting point for
the production of simplified bioactive molecules or to inform the production of synthetic small molecule libraries that are more
amenable to high throughput screening. Automated fractionation and characterization methods to improve screening, molecular
modeling programs to guide rational modification of natural products, and engineering strategies for heterologous production of natural
products in laboratory amenable organisms are making natural product drug discovery and development more accessible and may
lead to more programs in this area.
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Existing Products
There are numerous natural products that are approved for the treatment of a variety of diseases. Examples of approved natural
product therapeutics are listed in the table below.
Product
Disease
Notes
Lovastatin
Atherosclerosis/heart disease
First isolated from the mushroom
Aspergillus terreus in 1982
Paclitaxel
Cancer
First isolated from the bark of the Pacific
yew tree, Taxus brevifolia, in 1967
Ivermectin
(derivative of
natural product
avermectin)
Parasitic helminth infections:
Lymphatic filariasis and
Onchocerciasis
Avermectin was first isolated in 1978 from
the soil actinomycete Streptomyces
avermitilis
Artemisinin
Malaria
First described for treatment of fever in
traditional Chinese medicine. First
isolated from the leaves of the plant
Artemisia annua in 1972.
Streptomycin
Antibiotic
First isolated from the actinobacterium
Streptomyces griseus in 1943.
Natural Products as Non-Neglected Tropical Disease Therapeutics
Natural products and their derivatives have been used to treat a variety of non-neglected tropical diseases, including:
•
•
•
•
Cancer
Atherosclerosis/heart disease
Autoimmune diseases
Chronic pain
As natural products span a wide diversity of chemical scaffolds, mechanisms of actions, and molecular targets, it is difficult to draw
generalizations across this class. However, the diversity of diseases that have benefitted from natural product therapeutics is a
testament to this strategy for novel therapeutic discovery.
Natural Products as Neglected Tropical Disease Therapeutics
Natural products are used to treat a variety of neglected tropical diseases. Specific neglected tropical diseases with natural product
therapeutics include:
• Tuberculosis
• Lymphatic filariasis
• Malaria
Streptomycin, an antibiotic derived from the actinomycete Streptomyces griseus, was the first antibiotic successfully used to treat
tuberculosis. The discovery of streptomycin in 1943, followed by its first successful use for the treatment of tuberculosis in 1944, led to
the presentation of the 1952 Nobel Prize in Physiology or Medicine to Selman Waksman, the American scientist who made the
discovery.4 Although drug resistance ultimately limited the usefulness of streptomycin as a monotherapy, it is still used as part of
multidrug combination therapy for the treatment of tuberculosis with meningitis complications.
Ivermectin is a derivative of the natural product avermectin, a compound that was also isolated from an antinomycete of the genus
Streptomyces. It is used to treat a variety of infections caused by parasitic worms known as helminths, including strongyloides,
onchocerciasis, and lymphatic filariasis. Ivermectin has partial efficacy on other human helminth infections and is also used to treat
external infestations of scabies and lice. In animals, it is widely used for the treatment and prevention of heartworm.
One of the most interesting stories of natural product drug discovery for neglected diseases is that of artemisinin for the treatment of
malaria. Artemisinin is a naturally occurring chemical compound found in the leaves of the plant Artemisia annua. Records of the use of
this plant for the treatment of malaria date back nearly 2000 years, but the artemisinin compound was not extracted from the plant and
characterized until the 1970s. Development of artemisinin as a drug faced several challenges. Extraction of the compound from plants
was expensive, making the drug largely unaffordable to those in need. Chemical synthesis of the compound was achieved but proved
difficult and costly without much benefit over extraction. As an alternative, genetic engineering of yeast was used to create a yeast
strain that could produce the artemisinin synthetic intermediate, artemisinic acid.5 This method of production drastically reduced the
cost of artemisinin production. Artemisinin is now widely available as part of artemisinin combination therapies (ACTs). Multiple
semi-synthetic and synthetic derivatives are also now in use or in development for the treatment of malaria.
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References
1. Li JWH and Vederas JC (2009) “Drug discovery and natural products: end of an era or an endless frontier?” Science 325:
161-165.
2. Koehn FE and Carter GT (2005) “The evolving role of natural products in drug discovery.” Nature Reviews Drug Discovery 4:
206-220.
3. Chin YW (2006) “Drug Discovery from Natural Sources.” The AAPS Journal 8: E239-E253.
4. NobelPrize.org article “Tuberculosis,” available here.
5. Ro DK et al. (2006) “Production of the antimalarial drug precursor artemisinic acid in engineered yeast.” Nature 440: 940-943.
Get Involved
To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates,
changes, or corrections to the Global Health Primer website, please view our FAQs or contact us at [email protected].
Pipeline & Analysis
Get Involved
PIPELINE
Product/Research
Program
Developers
ASB010
Autoimmune Technologies
LLC
PYN-18
Phynova
Licochalcone A
Lica Pharmaceuticals
184045
ImCure Therapeutics
(formerly JJ Pharma)
Cry5B
University of California,
San Diego
Tryptanthrin
Global Alliance for TB Drug
On Hold
Development
Natural products
Global Alliance for TB Drug
Development
Institute of Microbiology
On Hold
Chinese Academy of
Sciences
Discovery
Pre-clinical
Phase I
Phase II
Phase III
ANALYSIS
Natural products are in use or in development for a variety of diseases. New natural products are in development for the treatment of
leishmaniasis, tuberculosis, and dengue fever. The pipeline above excludes artemisinin derivatives in development for malaria, but
more information on these products can be found under the malaria disease profile.
The relative strengths, weaknesses, opportunities, and risk for natural products that are currently in use or in development for
neglected tropical diseases are summarized here.
Strengths
Weaknesses
Opportunities
Risks
Natural product drug
discovery can be labor
intensive and expensive
Additional screening of
natural products against
all neglected tropical
diseases
Majority of programs are
very early stage, so
potential for successful
application in humans is
not known
Natural products
Relevant neglected
tropical diseases:
Malaria (multiple
artemisinin-related products
on market and in late stage
development)
Tuberculosis (streptomycin
on market; multiple products
in discovery stage of
development)
Dengue fever (ASB010 and
PYN-18, pre-clinical)
Leishmaniasis
(Licochalcone A,
pre-clinical)
With the exception of
malaria, new natural
product programs are
primarily focused on
novel or unknown
mechanisms of action
relative to approved
products for these
diseases which will
reduce the chance for
resistance
Mechanism of action of
natural products
screened against whole
cells rather than specific
targets can be difficult to
identify (e.g.,
mechanism of action of
artemisinin in malaria is
still not fully understood)
Generation of synthetic
chemical libraries based
on hits from discovery
stage natural product
programs
Identified natural
products may be
complex and difficult to
produce at low cost for
use in resource poor
settings
Get Involved
To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates,
changes, or corrections to the Global Health Primer website, please view our FAQs or contact us at [email protected].
Tools
Get Involved
Databases/Resources
There are numerous databases of natural product compound information including:
• Dictionary of Natural Products
• SuperNatural V2: A Natural Compound Database
• Natural Products Alerts
Assays
Assays and associated technologies to separate and analyze natural products are advancing. Representative examples include:1,2
• Automated fractionation, plating, and analysis of crude extracts to facilitate high throughput screening and bioactive compound
identification
• Concurrent screening of fractions using positive and negative selection (primarily to reduce false positives from natural products
that are already known)
• Advances in mass spectrometry and NMR analysis methods to identify bioactive compounds
For the most part, screening of natural products or fractionated biological materials to discover new natural product therapeutics is
primarily limited by the availability of screening assays for the disease of interest. More information on the availability of assays for
screening can be found under the tools section for each specific neglected tropical disease.
References
1. Li JWH and Vederas JC (2009) “Drug discovery and natural products: end of an era or an endless frontier?” Science 325:
161-165.
2. Koehn FE and Carter GT (2005) “The evolving role of natural products in drug discovery.” Nature Reviews Drug Discovery 4:
206-220.
Get Involved
To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates,
changes, or corrections to the Global Health Primer website, please view our FAQs or contact us at [email protected].
Product Details
184045
Synonyms:
184045
Notes:
Disease:
Tuberculosis (TB)
Target/Technology:
Natural products
Specific Indication:
Mechanism of Action:
Product Type:
Drug
Molecule Class:
Natural product
PRV Elegible?
Yes
Administration Route:
Clinical Trials:
Publications:
ASB010
Synonyms:
ASB010
Disease:
Dengue fever
Target/Technology:
Natural products
Specific Indication:
Mechanism of Action:
Product Type:
Drug
Molecule Class:
Administration Route:
PRV Elegible?
Yes
Notes:
Clinical Trials:
Publications:
Cry5B
Synonyms:
Cry5B
Notes:
Disease:
Soil-Transmitted Helminths: Ascariasis
and Trichuriasis
Target/Technology:
Natural products
Specific Indication:
Mechanism of Action:
Bacterial toxin
Product Type:
Drug
Molecule Class:
Recombinant protein
PRV Elegible?
Yes
Administration Route:
Clinical
Trials:
Publications:
Cry5B is a natural bacterial toxin that is currently used in genetically engineered food crops to
kill helminth pests. The protein is now being modified to kill soil transmitted helminths of
humans. There is potential to express the protein in common bacteria already used in foods,
such as lactobacillus used in yogurt, to treat human helminth infections.
Licochalcone A
Synonyms:
Licochalcone A
Disease:
Leishmaniasis
Target/Technology:
Natural products
Specific Indication:
Visceral (VL)
Mechanism of Action:
Product Type:
Drug
Molecule Class:
Natural product
Administration Route:
PRV Elegible?
Yes
Notes:
Clinical Trials:
Publications:
Natural products
Synonyms:
Natural products
Notes:
Disease:
Tuberculosis (TB)
Target/Technology:
Natural products
Specific Indication:
Mechanism of Action:
Product Type:
Drug
Molecule Class:
Natural product
PRV Elegible?
Yes
Administration Route:
Clinical Trials:
Publications:
PYN-18
Synonyms:
PYN-18
Disease:
Dengue fever
Target/Technology:
Natural products
Specific Indication:
Mechanism of Action:
Product Type:
Drug
Molecule Class:
Administration Route:
PRV Elegible?
Yes
Notes:
Clinical Trials:
Publications:
2020915
Tryptanthrin
Synonyms:
Tryptanthrin
Notes:
Disease:
Tuberculosis (TB)
Target/Technology:
Natural products
Specific Indication:
Mechanism of Action:
Product Type:
Drug
Molecule Class:
Natural product
PRV Elegible?
Yes
Administration Route:
Clinical Trials:
Publications: