Selective protein unfolding: a universal mechanism of action for the development of irreversible inhibitors

Askin, Samuel P.; Bond, Thomas E. H.; Sorenson, Alanna E.; Moreau, Morgane J. J.; Antony, Helma; Davis, Rohan A.; Schaeffer, Patrick M.

doi:10.1039/c8cc00090e

Cited by 14 publications

(9 citation statements)

References 28 publications

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“…The Davis Open Access Natural Product-Based Library consists of distinct compounds, the majority (53%) of which are natural products obtained primarily from Australian fungal, plant, and marine invertebrate sources (11)(12), as well as semi-synthetic natural product analogues (28%) and known commercial drugs or synthetic compounds inspired by natural products (19%). All compounds evaluated in this study were analyzed for purity prior to testing and shown to be > 95% pure.…”

Section: Chemical Libraries and Hit Compoundsmentioning

confidence: 99%

“…However, outside of computational studies, few natural products to date have been demonstrated to act on SARS-CoV-2 replication (10). To identify natural product-derived compounds that may inhibit entry across multiple SARS-CoV-2 variants, we developed an AlphaScreen-based RBD/ACE2 interaction assay to screen a pure compound library containing 512 natural products and derivatives sourced predominantly from plants, mushrooms and marine invertebrates of Australia, Papua New Guinea, and neighboring regions (11)(12). The top hits from this screen, which included the plant stilbenoids (-)-hopeaphenol, vatalbinoside A, and vaticanol B (Figure 1), were then assessed for in vitro mechanisms of action using SARS-CoV-2 pseudoviruses and antiviral efficacy using infectious SARS-CoV-2 variants encompassing parental and B.1.1.7 and B.1.351 variants.…”

Section: Introductionmentioning

confidence: 99%

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The natural stilbenoid (–)-hopeaphenol inhibits cellular entry of SARS-CoV-2 USA-WA1/2020, B.1.1.7 and B.1.351 variants

Tietjen¹,

Cassel²,

et al. 2021

Preprint

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Antivirals are urgently needed to combat the global SARS-CoV-2/COVID-19 pandemic, supplement existing vaccine efforts, and target emerging SARS-CoV-2 variants of concern. Small molecules that interfere with binding of the viral spike receptor binding domain (RBD) to the host ACE2 receptor may be effective inhibitors of SARS-CoV-2 cell entry. Here we screened 512 pure compounds derived from natural products using a high-throughput RBD/ACE2 binding assay and identified (-)-hopeaphenol, a resveratrol tetramer, in addition to vatalbinoside A and vaticanol B, as potent and selective inhibitors of RBD/ACE2 binding and viral entry. For example, (-)-hopeaphenol disrupted RBD/ACE2 binding with a 50% inhibitory concentration (IC50) of 0.11 uM in contrast to an IC50 of 28.3 uM against the unrelated host ligand/receptor binding pair PD-1/PD-L1 (selectivity index = 257.3). When assessed against the USA-WA1/2020 variant, (-)-hopeaphenol also inhibited entry of a VSVdeltaG-GFP reporter pseudovirus expressing SARS-CoV-2 spike into ACE2-expressing Vero-E6 cells and in vitro replication of infectious virus in cytopathic effect assays (IC50 = 10.2 uM) without cytotoxicity. Notably, (-)-hopeaphenol also inhibited two emerging variants of concern originating from the United Kingdom (B.1.1.7) and South Africa (B.1.351) in both cytopathic effect and spike-containing pseudovirus assays with similar (B.1.1.7) or improved (B.1.351) efficacies over the USA-WA1/2020 variant. These results identify (-)-hopeaphenol and related stilbenoid analogues as potent and selective inhibitors of viral entry across multiple SARS-CoV-2 variants including those with increased infectivity and/or reduced susceptibility to existing vaccines.

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Section: Chemical Libraries and Hit Compoundsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The natural stilbenoid (–)-hopeaphenol inhibits cellular entry of SARS-CoV-2 USA-WA1/2020, B.1.1.7 and B.1.351 variants

Tietjen¹,

Cassel²,

et al. 2021

Preprint

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“…To the best of our knowledge, these are the first examples of the derivatization of a benzylisoquinoline using Diversinate TM C–H functionalization chemistry. This unique library has been added to the Davis open-access natural product-based library for future drug discovery and chemical biology evaluations [41].…”

Section: Discussionmentioning

confidence: 99%

Reaction of Papaverine with Baran DiversinatesTM

et al. 2019

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The reaction of papaverine with a series of Baran DiversinatesTM is reported. Although the yields were low, it was possible to synthesize a small biodiscovery library using this plant alkaloid as a scaffold for late-stage C–H functionalization. Ten papaverine analogues (2–11), including seven new compounds, were synthesized. An unexpected radical-induced exchange reaction is reported where the dimethoxybenzyl group of papaverine was replaced by an alkyl group. This side reaction enabled the synthesis of additional novel fragments based on the isoquinoline scaffold, which is present in numerous natural products. Possible reasons for the poor yields in the DiversinateTM reactions with this particular scaffold are discussed.

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“…Among them, the genus, Alternaria , is a prominent representative, although it is usually known as a plant pathogen [ 2 ]. Altenusin is the characteristic metabolite of Alternaria sp., with a biphenyl skeleton, and has been reported to have antioxidant, antimicrobial, cytotoxic, biotin protein ligase inhibitory, FXR agonist, and tau protein aggregation inhibitory activities [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. To date, more than 15 altenusin derivatives have been discovered from fungal origins.…”

Section: Introductionmentioning

confidence: 99%

Two New Altenusin/Thiazole Hybrids and a New Benzothiazole Derivative from the Marine Sponge-Derived Fungus Alternaria sp. SCSIOS02F49

Ya-ping

Chen

et al. 2018

Molecules

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Two novel altenusin-thiazole hybrids named altenusinoides A and B (1 and 2), a new benzothiazole derivative (3), and three known altenusin derivatives (4–6) have been obtained from the solid culture of the marine sponge-derived fungal strain, Alternaria sp. SCSIOS02F49. The structures of these new compounds were characterized by NMR, HRESIMS, and X-ray single crystal analysis. Compounds 1 and 2 possess an unusual altenusin-thiazole-fused skeleton core (6/6/5), and compound 3 represents the first benzothiazole derivative from fungi. Compounds 4 and 5 showed significant DPPH free-radical-scavenging activities with the prominent IC50 values of 10.7 ± 0.09 μM and 100.6 ± 0.025 μM, respectively. Additionally, compound 5 exhibited COX-2 inhibitory activity with an IC50 value of 9.5 ± 0.08 μM.

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Selective protein unfolding: a universal mechanism of action for the development of irreversible inhibitors

Cited by 14 publications

References 28 publications

The natural stilbenoid (–)-hopeaphenol inhibits cellular entry of SARS-CoV-2 USA-WA1/2020, B.1.1.7 and B.1.351 variants

The natural stilbenoid (–)-hopeaphenol inhibits cellular entry of SARS-CoV-2 USA-WA1/2020, B.1.1.7 and B.1.351 variants

Reaction of Papaverine with Baran DiversinatesTM

Two New Altenusin/Thiazole Hybrids and a New Benzothiazole Derivative from the Marine Sponge-Derived Fungus Alternaria sp. SCSIOS02F49

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