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Harnessing Nature for drug discovery |
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News A screen of our Phytotitre library reveals new hits for Alzheimer’s disease Nobel prize awarded for natural product-based drug discovery, Discovery of new class of antibiotic through innovative natural product library screen, No decrease in rate of discovery of new natural product scaffolds between 1990 and 2015
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A screen of our Phytotitre library reveals new hits for Alzheimer’s disease Recently published work shows that sterubin, from Yerba santa, is four times more effective at neuroprotection than the previous best in class compound [1]. Alzheimer’s disease is the most common cause of dementia, and its incidence is increasing rapidly in ageing Western societies. It is caused by the progressive loss of neurons in the brain, resulting in long term cognitive decline. Neuronal loss is thought to arise from the exposure of neurons to diverse toxic stimuli which arise in lesions associated with the condition. As there are currently no therapies which cure or halt the progression of Alzheimer’s disease, there is a pressing need to identify compounds with potential to protect neurons from the toxic insults associated with Alzheimer’s disease. To address this, Fischer et al used a phenotypic screening approach to identify plant extracts from the Phytotitre library with potential to rescue cultured nerve cells from diverse toxic insults [1]. This phenotypic screening approach was chosen on the basis of its frequent success in identifying ‘hits’ with improved potential for translation compared to those found via single target screening approaches [2]. To maximise the potential utility of their hits, the team used a variety of assays to screen for agents with potential to protect against oxidative, inflammatory and other forms of neuronal insult. The primary screen examined the potential of plant extracts to protect cultured HT22 mouse hippocampal nerve cells from oxidative stress. Hits from this screen were then taken forward to assess their capacity to act as anti-inflammatory agents, by blocking the release of nitric oxide from LPS-challenged BV-2 microglial cells. Extracts were then tested for their potential to promote neurite outgrowth in rat PC12 cells, and protect against intracellular amyloid beta aggregation in the MC65 human nerve cell line model. Of 400 non-polar extracts tested, 9 showed significant neuroprotection in the primary screen at a dilution of 1:10,000 from stock (hit rate 2.2%). Two of these extracts were then found to demonstrate strong neurotrophic and anti-inflammatory activity, together with low endogenous cytotoxicity. One of the extracts, isolated from the shrub Yerba santa (Eriodictyon californicum), was taken forward for further tests. Activity guided separation of the active compound was achieved by HPLC, and the molecule was then identified as sterubin, by comparing MS/MS spectra. Purified sterubin was then shown to confer the same protective properties as the parent extract, with particularly promising results in the intracellular protein aggregate model of neurotoxicity. Mechanistic studies showed that sterubin exhibits little anti-oxidant capacity directly, but rather is a potent inducer of host cell defences against oxidative, and other stresses. Sterubin is a very liitle studied compound, and this report represents the first discovery of neuroprotective properties of the molecule. Promisingly, it was found to be 4 times more potent in their assays than fisetin, a compound currently considered to be a leading candidate for potential use as a neuroprotective drug for Alzheimer’s disease [3,4]. It also exhibits favourable properties (MWt, ClogP, tPSA etc) for potential use as a central nervous system drug. Taken together, the results of this study offer promising progress in the search for new therapies for Alzheimer’s disease, and further validate the utility of screening natural product libraries for even the most challenging of targets.
[1] Fischer W, Currais A, Liang Z, Pinto A, Maher
P. Old age-associated phenotypic screening for Alzheimer's disease drug
candidates identifies Sterubin as a potent neuroprotective compound from
Yerba santa. Redox Biol 21:101089 (2019) [2] Moffat JG, Vincent F, Lee JA, Eder J,
Prunotto M. Opportunities and challenges in phenotypic drug discovery:
an industry perspective. Nat Rev Drug Discov 16:531-543 (2017) [3] Currais A, Prior M, Dargusch R, Armando A,
Ehren J, Schubert D, Quehenberger O, Maher P. Modulation of p25 and
inflammatory pathways by fisetin maintains cognitive function in
Alzheimer's disease transgenic mice. Aging Cell 13:379-390 (2014) [4] Currais A, Farrokhi C, Dargusch R, Armando A,
Quehenberger O, Schubert D, Maher P. Fisetin reduces the impact of aging
on behavior and physiology in the rapidly aging SAMP8 mouse. J Gerentol
A Biol Sci Med Sci 73:299-307 (2018)
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