Identification of novel non-nucleoside vinyl-stilbene analogs as potent norovirus replication inhibitors with a potential host-targeting mechanism

Harmalkar, Dipesh S.; Lee, Sung‐Jin; Lu, Qili; Kim, Mi Il; Park, Jae-Hyung; Lee, Hwa Young; Park, Minkyung; Lee, Ahrim; Lee, Choong-Ho; Lee, Kyeong

doi:10.1016/j.ejmech.2019.111733

Cited by 11 publications

(15 citation statements)

References 18 publications

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“…Notably, preliminary in vivo studies reported in the literature have shown that in general, stilbenoids show low bioavailability and undergo extensive metabolism and it has been pointed out that bioconverted forms of polyphenols, (phase I and II metabolism) may probably have more importance than the parent compound found in the diet or administered in therapy. In many cases, synthetic efforts produced stilbene derivatives with greater potency than their parent compounds, allowing to expand knowledge on modes of action and to deepen structure-activity relationship studies of the most active compounds [39,70,76,77,82,91].…”

Section: Discussionmentioning

confidence: 99%

“…Harmalkar et al performed the total synthesis of the natural gramistilbenoids A, B, C, and of their analogues (25e27) ( Fig. 16) [91]. The stilbenoid 26 bearing a vinyl group displayed a moderate inhibitory activity against HNV replication on HG23 cells.…”

Section: Norovirusmentioning

confidence: 99%

“…An optimum of antiviral potency, low cytotoxicity and highest metabolic stability in human and mouse liver microsomes was achieved in compound 28 (EC 50 ¼ 2.43 mM, CC 50 < 100 mM). 28 inhibited the viral RNA genome replication probably involving the heat shock factor 1 (HSF-1) dependent stress inducible pathway, a host signal target and a new mechanism of action that may lead to the development of new anti-HNV drugs [91].…”

Section: Norovirusmentioning

confidence: 99%

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Natural and nature-inspired stilbenoids as antiviral agents

Mattio

Catinella

Pinto

et al. 2020

European Journal of Medicinal Chemistry

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Viruses continue to be a major threat to human health. In the last century, pandemics occurred and resulted in significant mortality and morbidity. Natural products have been largely screened as source of inspiration for new antiviral agents. Within the huge class of plant secondary metabolites, resveratrolderived stilbenoids present a wide structural diversity and mediate a great number of biological responses relevant for human health. However, whilst the antiviral activity of resveratrol has been extensively studied, little is known about the efficacy of its monomeric and oligomeric derivatives. The purpose of this review is to provide an overview of the achievements in this field, with particular emphasis on the source, chemical structures and the mechanism of action of resveratrol-derived stilbenoids against the most challenging viruses. The collected results highlight the therapeutic versatility of stilbene-containing compounds and provide a prospective insight into their potential development as antiviral agents.

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Section: Discussionmentioning

confidence: 99%

Section: Norovirusmentioning

confidence: 99%

Section: Norovirusmentioning

confidence: 99%

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Natural and nature-inspired stilbenoids as antiviral agents

Mattio

Catinella

Pinto

et al. 2020

European Journal of Medicinal Chemistry

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“…More recently, Harmalkar and colleagues (2019) reported the identification of non-nucleoside vinyl-stilbene analogs as potent norovirus replication inhibitors [ 116 ]. Some compounds were subjected to structural modifications via an empirical medicinal chemistry approach to improve their anti-noroviral activity.…”

Section: Non-enveloped Virusesmentioning

confidence: 99%

“…Some compounds were subjected to structural modifications via an empirical medicinal chemistry approach to improve their anti-noroviral activity. Then, new replication inhibition assays were performed using the HG23 cell line, and the results showed that vinyl stilbene compounds may be optimal for inhibitory activity against norovirus replication [ 116 ]. The use of the NV replicon system in the studies presented herein enabled the identification of different classes of compounds with antiviral activities and may facilitate the development of effective anti-norovirus therapeutics in the near future.…”

Section: Non-enveloped Virusesmentioning

confidence: 99%

Reporter Replicons for Antiviral Drug Discovery against Positive Single-Stranded RNA Viruses

Fernandes

Freire

Bueno

et al. 2020

Viruses

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Single-stranded positive RNA ((+) ssRNA) viruses include several important human pathogens. Some members are responsible for large outbreaks, such as Zika virus, West Nile virus, SARS-CoV, and SARS-CoV-2, while others are endemic, causing an enormous global health burden. Since vaccines or specific treatments are not available for most viral infections, the discovery of direct-acting antivirals (DAA) is an urgent need. Still, the low-throughput nature of and biosafety concerns related to traditional antiviral assays hinders the discovery of new inhibitors. With the advances of reverse genetics, reporter replicon systems have become an alternative tool for the screening of DAAs. Herein, we review decades of the use of (+) ssRNA viruses replicon systems for the discovery of antiviral agents. We summarize different strategies used to develop those systems, as well as highlight some of the most promising inhibitors identified by the method. Despite the genetic alterations introduced, reporter replicons have been shown to be reliable systems for screening and identification of viral replication inhibitors and, therefore, an important tool for the discovery of new DAAs.

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