A natural product compound inhibits coronaviral replication in vitro by binding to the conserved Nsp9 SARS-CoV-2 protein

Littler, Dene R.; Liu, Miaomiao; McAuley, Julie; Lowery, Shea A.; Illing, Patricia T.; Gully, Benjamin S.; Purcell, Anthony W.; Chandrashekaran, Indu R.; Perlman, Stanley; Purcell, Damian F. J.; Quinn, Ronald J.; Rossjohn, Jamie

doi:10.1016/j.jbc.2021.101362

Cited by 39 publications

(51 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our previous study, compound 1 was crystallized with Nsp9 COVID19 and a covalent bond was found to occur between the bridging enone group of compound 1 and the first residue of the strand Cys73. 8 To investigate whether Cys73 is required for the protein–ligand complex formation, ligand binding experiments of compounds 1 and 2 and a Cys73 to a Ser mutant (Nsp9 C73S ) were conducted ( Figure 7 ). Protein–ligand complexes were detected from both compounds to the Nsp9 C73S mutant protein at >50 μM ligand addition; however, compared to the wild-type protein, a significantly lower amount of protein–ligand complex was observed.…”

Section: Resultsmentioning

confidence: 99%

“…The structure of Nsp9 used for molecular docking was published in our previous paper 8 and can be accessed from the Protein Data Bank (7N3K). Docking was performed using the program medusadock 2.…”

Section: Methodsmentioning

confidence: 99%

“… 8 The compound was found to have an in vitro anti-viral activity with a 50% effective concentration (EC 50 ) of 25.2 μM for the VIC01 strain in an in vitro coronaviral replication assay. 8 …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Binding Studies of the Prodrug HAO472 to SARS-Cov-2 Nsp9 and Variants

et al. 2022

Self Cite

View full text Add to dashboard Cite

SARS-CoV-2 (COVID-19) has infected over 219 million people and caused the death of over 4.55 million worldwide. In a previous screen of a natural product library against purified SARS-CoV-2 Nsp9 using a native mass spectrometry-based approach, we identified an ent- kaurane natural product, oridonin ( 1 ), with micromolar affinities. In this work, we have found that the prodrug HAO472 ( 2 ) directly binds to Nsp9, establishing replacement of the labile ester with a bioisostere as a candidate drug strategy. We further tested 1 and its clinical analogue 2 against two Nsp9 variants from human coronavirus 229E (HCoV-229E) and ferret systemic coronavirus F56 (FSCoV-F56). Both compounds showed significant binding selectivity to COVID-19 and HCoV-229E Nsp9 over FSCoV-F56 Nsp9, confirming the covalent bond with Cys73.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Binding Studies of the Prodrug HAO472 to SARS-Cov-2 Nsp9 and Variants

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Small molecules could interfere with NiRAN activity by binding to nsp9, AS2, or an allosteric site. A natural product inhibitor that binds to nsp9 has been recently identified [40], and structures with ligands bound to AS2 [12,18,35,41,42] could guide design of NiRAN inhibitors. An in silico docking study identified several putative NiRAN ligands among FDA-approved protease and kinase inhibitors as well as antibiotics [30].…”

Section: Sars-cov-2 Niran Domain As a Target For Small-molecule Ligandsmentioning

confidence: 99%

Going Retro, Going Viral: Experiences and Lessons in Drug Discovery from COVID-19

Wang

Svetlov²,

Bartikofsky

et al. 2022

Molecules

View full text Add to dashboard Cite

The severity of the COVID-19 pandemic and the pace of its global spread have motivated researchers to opt for repurposing existing drugs against SARS-CoV-2 rather than discover or develop novel ones. For reasons of speed, throughput, and cost-effectiveness, virtual screening campaigns, relying heavily on in silico docking, have dominated published reports. A particular focus as a drug target has been the principal active site (i.e., RNA synthesis) of RNA-dependent RNA polymerase (RdRp), despite the existence of a second, and also indispensable, active site in the same enzyme. Here we report the results of our experimental interrogation of several small-molecule inhibitors, including natural products proposed to be effective by in silico studies. Notably, we find that two antibiotics in clinical use, fidaxomicin and rifabutin, inhibit RNA synthesis by SARS-CoV-2 RdRp in vitro and inhibit viral replication in cell culture. However, our mutagenesis studies contradict the binding sites predicted computationally. We discuss the implications of these and other findings for computational studies predicting the binding of ligands to large and flexible protein complexes and therefore for drug discovery or repurposing efforts utilizing such studies. Finally, we suggest several improvements on such efforts ongoing against SARS-CoV-2 and future pathogens as they arise.

show abstract

“…nsp9 of SARS-CoV-2 can bind to the nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain relating the viral replication and transcription ( Kumar M. et al, 2021 ), and it was also considered to be the therapy target for COVID-19 treatment ( Zhang et al, 2020 ; Kumar et al, 2021b ). There were several studies to screen the potential candidate compounds to bind or act on nsp9 by in silico tools ( Barros et al, 2020 ; Chandra et al, 2021 ; Junior et al, 2021 ), and one in vitro cellular assay showed the inhibition on nsp9 can reduce the viral replication of SARS-CoV-2 ( Littler et al, 2021 ). The molecular docking results showed that curcumin can bind to the ligand binding site of nsp9, and curcumin can form about 11 interaction sites with nsp9 ( Kumar et al, 2021b ).…”

Section: Introductionmentioning

confidence: 99%

Pharmaceutical Prospects of Curcuminoids for the Remedy of COVID-19: Truth or Myth

Fu¹,

Kang³

et al. 2022

Front. Pharmacol.

View full text Add to dashboard Cite

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is a positive-strand RNA virus, and has rapidly spread worldwide as a pandemic. The vaccines, repurposed drugs, and specific treatments have led to a surge of novel therapies and guidelines nowadays; however, the epidemic of COVID-19 is not yet fully combated and is still in a vital crisis. In repositioning drugs, natural products are gaining attention because of the large therapeutic window and potent antiviral, immunomodulatory, anti-inflammatory, and antioxidant properties. Of note, the predominant curcumoid extracted from turmeric (Curcuma longa L.) including phenolic curcumin influences multiple signaling pathways and has demonstrated to possess anti-inflammatory, antioxidant, antimicrobial, hypoglycemic, wound healing, chemopreventive, chemosensitizing, and radiosensitizing spectrums. In this review, all pieces of current information related to curcumin-used for the treatment and prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through in vitro, in vivo, and in silico studies, clinical trials, and new formulation designs are retrieved to re-evaluate the applications based on the pharmaceutical efficacy of clinical therapy and to provide deep insights into knowledge and strategy about the curcumin’s role as an immune booster, inflammatory modulator, and therapeutic agent against COVID-19. Moreover, this study will also afford a favorable application or approach with evidence based on the drug discovery and development, pharmacology, functional foods, and nutraceuticals for effectively fighting the COVID-19 pandemic.

show abstract

A natural product compound inhibits coronaviral replication in vitro by binding to the conserved Nsp9 SARS-CoV-2 protein

Cited by 39 publications

References 52 publications

Binding Studies of the Prodrug HAO472 to SARS-Cov-2 Nsp9 and Variants

Binding Studies of the Prodrug HAO472 to SARS-Cov-2 Nsp9 and Variants

Going Retro, Going Viral: Experiences and Lessons in Drug Discovery from COVID-19

Pharmaceutical Prospects of Curcuminoids for the Remedy of COVID-19: Truth or Myth

Contact Info

Product

Resources

About