Tetrandrine – A molecule of wide bioactivity

Bhagya, N.; Chandrashekar, K. R.

doi:10.1016/j.phytochem.2016.02.005

Cited by 186 publications

(126 citation statements)

References 83 publications

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“…Identification that PyVs share a conserved requirement with EBOV suggests that NAADP-sensitive TPC inhibition represents a therapeutic target for viruses and pathogens that traffic through the ER during entry stages. Although tetrandrine is not widely available and there are currently limited studies into the efficacy of treatment in vivo , the identification of endosomal-ER fusion as a requirement for a variety of pathogens provides a common target that could potentially be exploited (60, 61).…”

Section: Discussionmentioning

confidence: 99%

A requirement for Potassium and Calcium Channels during the Endosomal Trafficking of Polyomavirus Virions

Dobson

Mankouri

Whitehouse

2019

Preprint

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19Following internalisation viruses have to escape the endocytic pathway and deliver their 20 genomes to initiate replication. Members of the Polyomaviridae transit through the 21 endolysosomal network and through the endoplasmic reticulum (ER), from which heavily 22 degraded capsids escape into the cytoplasm prior to nuclear entry. Acidification of 23 endosomes and ER entry are essential in the lifecycle of polyomaviruses, however many 24 mechanistic requirements are yet to be elucidated. Alteration of endocytic pH relies upon the 25 activity of ion channels. Using two polyomaviruses with differing capsid architecture, namely 26 Simian virus 40 (SV40) and Merkel cell polyomavirus (MCPyV), we firstly describe methods 27 to rapidly quantify infection using an IncuCyte ZOOM instrument, prior to investigating the 28 role of K + and Ca 2+ channels during early stages of infection. Broad spectrum inhibitors 29 identified that MCPyV, but not SV40, is sensitive to K + channel modulation. In contrast, both 30 viruses are restricted by the broad spectrum Ca 2+ channel inhibitor verapamil, however 31 specific targeting of transient or long lasting Ca 2+ channel subfamilies had no detrimental 32 effect. Further investigation revealed that tetrandrine blockage of two-pore channels (TPCs), 33the activity of which is essential for endolysosomal-ER fusion, ablates infectivity of both 34 MCPyV and SV40 by preventing disassembly of the capsid, which is required for the 35 exposure of minor capsid protein nuclear signals necessary for nuclear transport. This study 36 therefore identifies a novel target to restrict the entry of polyomaviruses. 37 IMPORTANCE 38Polyomaviruses establish ubiquitous, asymptomatic infection in their host. However, in the 39 immunocompromised these viruses can cause a range of potentially fatal diseases. Through 40 the use of SV40 and MCPyV, two polyomaviruses with different capsid organisation, we 41 have investigated the role of ion channels during infection. Here, we show that Ca 2+ channel 42 activity is essential for both polyomaviruses and that MCPyV is also sensitive to K + channel 43 blockage, highlighting new mechanistic requirements of ion channels during polyomavirus 44 infection. In particular, tetrandrine blockage of endolysosomal-ER fusion is highlighted as an 45 essential modulator of both SV40 and MCPyV. Given that the role of ion channels in disease 46 have been well characterised, there is a large panel of clinically available therapeutics that Polyomaviruses (PyVs) are small double stranded DNA viruses that establish persistent 51 infections in their hosts. Whilst infections are generally asymptomatic, PyVs can cause 52 severe disease in the immunosuppressed. Common examples include BKPyV-associated 53 nephropathy and haemorrhagic cystitis, and JCPyV-induced progressive multifocal 54 leukoencephalopathy (PML) (1-3).55 In ~80% of Merkel cell carcinoma (MCC) cases, Merkel cell PyV (MCPyV) infection, clonal 56 integration and UV-mediated mutation of the viral genome occur prior to tumour c...

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Section: Discussionmentioning

confidence: 99%

A requirement for Potassium and Calcium Channels during the Endosomal Trafficking of Polyomavirus Virions

Dobson

Mankouri

Whitehouse

2019

Preprint

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“…To date, the published literature has focused principally on the alkaloids and extracts of S. tetrandra. The molecules that have received the greatest in-depth study of their pharmacological activity are tetrandrine (Yang et al 2018a;Bhagya and Chandrashekar 2016;Wang et al 2017a;Xing et al 2014;Cai et al 2011), fangchinoline (Desgrouas et al 2014a;Wang et al 2017a;Xing et al 2014) and cepharanthine (Bailly 2019;Wang et al 2017a). Not only are these compounds found in S. tetrandra, but also in other plants known to have medicinal properties (Table 2).…”

Section: Pharmacological Propertiesmentioning

confidence: 99%

A critical review: traditional uses, phytochemistry, pharmacology and toxicology of Stephania tetrandra S. Moore (Fen Fang Ji)

2020

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Stephania tetrandra S. Moore (S. tetrandra) is distributed widely in tropical and subtropical regions of Asia and Africa. The root of this plant is known in Chinese as ''Fen Fang Ji''. It is commonly used in traditional Chinese medicine to treat arthralgia caused by rheumatism, wet beriberi, dysuria, eczema and inflamed sores. Although promising reports have been published on the various chemical constituents and activities of S. tetrandra, no review comprehensively summarizes its traditional uses, phytochemistry, pharmacology and toxicology. Therefore, the review aims to provide a critical and comprehensive evaluation of the traditional use, phytochemistry, pharmacological properties, pharmacokinetics and toxicology of S. tetrandra in China, and meaningful guidelines for future investigations.

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“…17 It has been demonstrated that low pH is required for the GP-mediated membrane fusion. 2), a very well-known remedy in Traditional Chinese Medicine (TCM) for the treatment of a number of diseases such as tuberculosis, dysentery, malaria, cancer, and fever, 19 isolated from different species of plants from the Menispermaceae family, was shown to inhibit EBOV entry into host cells and infection of human macrophages (EC 50 ¼ 55 nM) by binding to TPC. 2) and clathrin-mediated endocytosis chlorpromazine have been shown to inhibit EBOV entry into the host cells in an in vitro replication-competent viral assay (inferred EC 50 values around 10 nM and 13 μM, respectively), providing a promising scaffold for the development of novel EBOV therapeutics.…”

Section: Endocytosis And/or Macropinocytosis Inhibitorsmentioning

confidence: 99%

Antiviral Agents Against Ebola Virus Infection: Repositioning Old Drugs and Finding Novel Small Molecules

Fanunza

Frau

Corona

et al. 2018

Annual Reports in Medicinal Chemistry

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Tetrandrine – A molecule of wide bioactivity

Cited by 186 publications

References 83 publications

A requirement for Potassium and Calcium Channels during the Endosomal Trafficking of Polyomavirus Virions

A requirement for Potassium and Calcium Channels during the Endosomal Trafficking of Polyomavirus Virions

A critical review: traditional uses, phytochemistry, pharmacology and toxicology of Stephania tetrandra S. Moore (Fen Fang Ji)

Antiviral Agents Against Ebola Virus Infection: Repositioning Old Drugs and Finding Novel Small Molecules

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