Divergent synthesis of thapsigargin analogs

Chu, Hang; Dünstl, Georg; Felding, Jakob; Baran, Phil S.

doi:10.1016/j.bmcl.2018.03.065

Cited by 13 publications

(12 citation statements)

References 28 publications

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“…The Ca 2+ mobilizing and cytotoxic features of plant-derived thapsigargin have been studied for 40 years 86 , 87 . Several analogs have already been designed and efficient and scalable purification or synthesis is now available for application in humans 88 – 90 . Recently, a protease-cleavable prodrug of thapsigargin, mipsagargin, has been evaluated in phase I and II clinical trials for prostate cancer 86 , 91 – 93 .…”

Section: Discussionmentioning

confidence: 99%

Multi-level inhibition of coronavirus replication by chemical ER stress

et al. 2021

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Coronaviruses (CoVs) are important human pathogens for which no specific treatment is available. Here, we provide evidence that pharmacological reprogramming of ER stress pathways can be exploited to suppress CoV replication. The ER stress inducer thapsigargin efficiently inhibits coronavirus (HCoV-229E, MERS-CoV, SARS-CoV-2) replication in different cell types including primary differentiated human bronchial epithelial cells, (partially) reverses the virus-induced translational shut-down, improves viability of infected cells and counteracts the CoV-mediated downregulation of IRE1α and the ER chaperone BiP. Proteome-wide analyses revealed specific pathways, protein networks and components that likely mediate the thapsigargin-induced antiviral state, including essential (HERPUD1) or novel (UBA6 and ZNF622) factors of ER quality control, and ER-associated protein degradation complexes. Additionally, thapsigargin blocks the CoV-induced selective autophagic flux involving p62/SQSTM1. The data show that thapsigargin hits several central mechanisms required for CoV replication, suggesting that this compound (or derivatives thereof) may be developed into broad-spectrum anti-CoV drugs.

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Section: Discussionmentioning

confidence: 99%

Multi-level inhibition of coronavirus replication by chemical ER stress

et al. 2021

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“…The Ca 2+ mobilizing and cytotoxic features of plantderived thapsigargin have been studied for 40 years (Andersen et al, 2015;Patkar et al, 1979). Several analogues have already been designed and efficient and scalable purification or synthesis is now available for application in humans (Chu et al, 2018;Chu et al, 2017;Lopez et al, 2018). Recently, a protease-cleavable prodrug of thapsigargin, mipsagargin, has been evaluated in phase I and II clinical trials for prostate cancer (Doan et al, 2015;Mahalingam et al, 2019;Mahalingam et al, 2016;Patkar et al, 1979).…”

Section: Discussionmentioning

confidence: 99%

Inhibiting coronavirus replication in cultured cells by chemical ER stress

Shaban

Müller

Mayr-Buro

et al. 2020

Preprint

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Coronaviruses (CoVs) are important human pathogens for which no specific treatment is available. Here, we provide evidence that pharmacological reprogramming of ER stress pathways can be exploited to suppress CoV replication. We found that the ER stress inducer thapsigargin efficiently inhibits coronavirus (HCoV-229E, MERS-CoV, SARS-CoV-2) replication in different cell types, (partially) restores the virus-induced translational shut-down, and counteracts the CoV-mediated downregulation of IRE1α and the ER chaperone BiP. Proteome-wide data sets revealed specific pathways, protein networks and components that likely mediate the thapsigargin-induced antiviral state, including HERPUD1, an essential factor of ER quality control, and ER-associated protein degradation complexes. The data show that thapsigargin hits a central mechanism required for CoV replication, suggesting that thapsigargin (or derivatives thereof) may be developed into broad-spectrum anti-CoV drugs.One Sentence Summary / Running titleSuppression of coronavirus replication through thapsigargin-regulated ER stress, ERQC / ERAD and metabolic pathways

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“…Many natural products are lipidated, and their bioactivity is often significantly reduced when the lipid tail is altered or removed. 9,11,13 To systematically study how widespread this modification is and what type of lipids are most prevalent, we sought to characterize lipidated natural products (Figure 2A).…”

Section: Chemoinformatic Characterization Of the 'Natural Product Lip...mentioning

confidence: 99%

“…Natural products, on the other hand commonly exhibit lipid functionalizations that fine-tune their pharmacokinetic and/or pharmacodynamic properties. Well known examples include bryostatin, 9,10 thapsigargin 11 , daptomycin, 12 and phorbol ester 13 . In addition to membrane permeability, direct drug-membrane interactions play key roles in targeting proteins that are embedded in or associated with biological membranes.…”

Section: Introductionmentioning

confidence: 99%

Medium-Length Lipids Facilitate Cell-Permeability and Bioactivity

Capecchi

Hinnah²,

Petit-Jacques

et al. 2021

Preprint

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The majority of bioactive molecules act on membrane proteins or intracellular targets and therefore needs to partition into or cross biological membranes. Natural products often exhibit lipid modifications to facilitate critical molecule-membrane interactions and in many cases their bioactivity is markedly reduced upon removal of a lipid group. However, despite its importance in nature, lipid-conjugation of small molecules is not commonly used in chemical biology and medicinal chemistry, and the effect of such conjugation has not been systematically studied. To understand the composition of lipids found in natural products, we carried out a chemoinformatic characterization of the ‘natural product lipidome’. According to this analysis, lipidated natural products predominantly contain saturated linear medium-length lipids, which are significantly shorter than those found in membranes and lipidated proteins. To study the usefulness of such modifications in probe design, we systematically explored the effect of lipid conjugation on five different small molecule chemotypes and find that permeability, cellular retention, subcellular localization, and bioactivity can be significantly modulated depending on the type of lipid tail used. We demonstrate that medium-length lipid tails can render impermeable molecules cell-permeable and switch on their bioactivity. Saturated medium-length lipids (e.g. C10) are found to be ideal for the bioactivity of small molecules in mammalian cells, while saturated long-chain lipids (e.g. C18) often significantly reduce bioavailability and activity. Together, our findings suggest that conjugation of small molecules with medium-length lipids could be a powerful strategy for the design of probes and drugs.

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Divergent synthesis of thapsigargin analogs

Cited by 13 publications

References 28 publications

Multi-level inhibition of coronavirus replication by chemical ER stress

Multi-level inhibition of coronavirus replication by chemical ER stress

Inhibiting coronavirus replication in cultured cells by chemical ER stress

Medium-Length Lipids Facilitate Cell-Permeability and Bioactivity

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