Elsevier

Biotechnology Advances

Volume 33, Issue 8, December 2015, Pages 1582-1614
Biotechnology Advances

Research review paper
Discovery and resupply of pharmacologically active plant-derived natural products: A review

https://doi.org/10.1016/j.biotechadv.2015.08.001Get rights and content
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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.

Abbreviations

4CL
4-coumaroyl CoA ligase
ADME/T
absorption, distribution, metabolism, excretion (and toxicity)
BIA
benzylisoquinoline alkaloid
C4H
cinnamate 4-hydroxylase
CoA
coenzyme A
CRISPR/Cas9
clustered regulatory interspaced short palindromic repeat/CRISPR associated protein 9
DMPP
dimethylallyl-pyrophosphate
DNP
Dictionary of Natural Products
DNTI
Drugs from Nature Targeting Inflammation
EMA
European Medicines Agency
FDA
US Food and Drug Administration
GGPP
geranylgeranyl diphosphate
GPCR
G-protein coupled receptor
GC
gas chromatography
HPLC
high performance liquid chromatography
HTS
high-throughput screening
iNOS
inducible nitric oxide synthase
IPP
isopentenyl-pyrophosphate
MEP
2C-methyl-d-erythriol-4-phosphate
MS
mass spectrometry
NCI
(US) National Cancer Institute
NCT
National Clinical Trial
NME
new molecular entity
NMR
nuclear magnetic resonance
NPD
Natural Product Database
OPLS-DA
orthogonal projection to latent structures discriminant analysis
PAL
phenylalanine ammonia lyase
PLS-DA
partial least square regression modeling discriminant analysis
PPAR
peroxisome proliferator-activated receptor
QSAR
quantitative structure activity relationship
TAL
tyrosine ammonia lyase
TALEN
transcription activator-like effector nuclease
TCM
traditional Chinese medicine
THC
tetrahydrocannabinol
SHE
safety, health, and environment

Keywords

Natural products
Plants
Drug discovery
Phytochemistry
Pharmacology
Medicine
Ethnopharmacology
Computer modeling
Organic synthesis
Plant biotechnology

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1

These authors contributed equally to this work.