The future of plant drug discovery

Littleton, John M.

doi:10.1517/17460441.2.5.673

Cited by 15 publications

(16 citation statements)

References 63 publications

(56 reference statements)

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“…High-Throughput Screening (HTS) is a standard method for hit discovery for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry [13]. Using robotics, data processing and control software, liquid handling devices, and sensitive detectors, HTS allows a researcher to quickly conduct millions of biochemical, genetic or pharmacological tests.…”

Section: High-throughput Screeningmentioning

confidence: 99%

The Success of Natural Products in Drug Discovery

Lahlou¹

2013

464

262

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Drug discovery leading to robust and viable lead candidates' remains a challenging scientific task, which is the transition from a screening hit to a drug candidate, requires expertise and experience. Natural products and their derivatives have been recognized for many years as a source of therapeutic agents and of structural diversity. However, in addition to their chemical structure diversity and their biodiversity, the development of new technologies has revolutionized the screening of natural products in discovering new drugs. Applying these technologies compensates for the inherent limitations of natural products and offers a unique opportunity to re-establish natural products as a major source for drug discovery. The present article attempts to describe the utilization of compounds derived from natural resources as drug candidates, with a focus on the success of these resources in the process of finding and discovering new and effective drug compounds, an approach commonly referred to as "natural product drug discovery".

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Section: High-throughput Screeningmentioning

confidence: 99%

The Success of Natural Products in Drug Discovery

Lahlou¹

2013

464

262

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“…In plants, metabolites active at nicAchRs are believed to function as chemical defenses against herbivorous insects [2–4]. Nicotine (NIC) is a well-known example of a naturally occurring insecticide present in Nicotiana tabacum (tobacco) that, upon ingestion, targets and activates nicAchRs present in the insect central nervous system (CNS) producing aversive stimuli and/or death [2, 4]. NIC also activates nicAchRs present in the human CNS, which underlies its rewarding and neuroprotective properties [4, 5].…”

Section: Introductionmentioning

confidence: 99%

“…Nicotine (NIC) is a well-known example of a naturally occurring insecticide present in Nicotiana tabacum (tobacco) that, upon ingestion, targets and activates nicAchRs present in the insect central nervous system (CNS) producing aversive stimuli and/or death [2, 4]. NIC also activates nicAchRs present in the human CNS, which underlies its rewarding and neuroprotective properties [4, 5]. The latter effect has generated interest in the development of nicAchR agonists as neuroprotective agents [6–13].…”

Section: Introductionmentioning

confidence: 99%

Novel multifunctional pharmacology of lobinaline, the major alkaloid from Lobelia cardinalis

et al. 2016

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In screening a library of plant extracts from ~1000 species native to the Southeastern United States, Lobelia cardinalis was identified as containing nicotinic acetylcholine receptor (nicAchR) binding activity which was relatively non-selective for the α4β2- and α7-nicAchR subtypes. This nicAchR binding profile is atypical for plant-derived nicAchR ligands, the majority of which are highly selective for α4β2-nicAchRs. Its potential therapeutic relevance is noteworthy since agonism of α4β2- and α7-nicAchRs is associated with anti-inflammatory and neuroprotective properties. Bioassay-guided fractionation of L. cardinalis extracts led to the identification of lobinaline, a complex binitrogenous alkaloid, as the main source of the unique nicAchR binding profile. Purified lobinaline was a potent free radical scavenger, displayed similar binding affinity at α4β2- and α7-nicAchRs, exhibited agonist activity at nicAchRs in SH-SY5Y cells, and inhibited [3H]-dopamine (DA) uptake in rat striatal synaptosomes. Lobinaline significantly increased fractional [3H] release from superfused rat striatal slices preloaded with [3H]-DA, an effect that was inhibited by the non-selective nicAchR antagonist mecamylamine. In vivo electrochemical studies in urethane-anesthetized rats demonstrated that lobinaline locally applied in the striatum significantly prolonged clearance of exogenous DA by the dopamine transporter (DAT). In contrast, lobeline, the most thoroughly investigated Lobelia alkaloid, is an α4β2-nicAchR antagonist, a poor free radical scavenger, and is a less potent DAT inhibitor. These previously unreported multifunctional effects of lobi-naline make it of interest as a lead to develop therapeutics for neuropathological disorders that involve free radical generation, cholinergic, and dopaminergic neurotransmission. These include neurodegenerative conditions, such as Parkinson’s disease, and drug abuse.

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“…The pharmaceutical industry is increasingly abandoning plants as a source of drugs (see Littleton 2007). One reason is that many bioactive plant metabolites are too complex for convenient chemical synthesis, making them difficult to optimize for interaction with the molecular target.…”

Section: Introductionmentioning

confidence: 99%

“…These may be metabolites that are present in the wild-type plant or, if a mutation alters a relevant biosynthetic pathway, then “novel” active metabolites with enhanced activity at the target may be generated (Rogers et al 2003). Target proteins have previously been expressed in plant cells as screens (Littleton 2007, Doukhanina et al 2007, Zhao et al 2012, Gunjan et al 2013), but this is the first report in which survival of mutant plant cells expressing a foreign target protein has been used to direct secondary metabolism toward a specific pharmacological phenotype. Proof of concept uses Lobelia cardinalis , which contains lobinaline, a novel inhibitor of the human dopamine transporter (DAT) (Littleton et al 2004, Brown et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Target-directed discovery and production of pharmaceuticals in transgenic mutant plant cells

Brown

Rogers

Gunjan

et al. 2016

Journal of Biotechnology

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Plants are a source of complex bioactive compounds, with value as pharmaceuticals, or leads for synthetic modification. Many of these secondary metabolites have evolved as defenses against competing organisms. and their pharmaceutical value is “accidental”, resulting from homology between target proteins in these competitors, and human molecular therapeutic targets. Here we show that it is possible to use mutation and selection of plant cells to re-direct their “evolution” toward metabolites that interact with the therapeutic target proteins themselves. This is achieved by expressing the human target protein in plant cells, and selecting mutants for survival based on the interaction of their metabolome with this target. This report describes the successful evolution of hairy root cultures of a Lobelia species toward increased biosynthesis of metabolites that inhibit the human dopamine transporter protein. Many of the resulting selected mutants are overproducing the active metabolite found in the wild-type plant, but others overproduce active metabolites that are not readily detectable in non-mutants. This technology can access the whole genomic capability of a plant species to biosynthesize metabolites with a specific target. It has potential value as a novel platform for plant drug discovery and production, or as a means of optimizing the therapeutic value of medicinal plant extracts.

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The future of plant drug discovery

Cited by 15 publications

References 63 publications

The Success of Natural Products in Drug Discovery

The Success of Natural Products in Drug Discovery

Novel multifunctional pharmacology of lobinaline, the major alkaloid from Lobelia cardinalis

Target-directed discovery and production of pharmaceuticals in transgenic mutant plant cells

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