Amilorides inhibit SARS-CoV-2 replication in vitro by targeting RNA structures

Zafferani, Martina; Haddad, Christina; Luo, Le; Davila‐Calderon, Jesse; Chiu, Liang‐Yuan; Mugisha, Christian Shema; Monaghan, Adeline G; Kennedy, Andrew; Yesselman, Joseph D.; Gifford, Robert J.; Tai, Andrew W.; Kutluay, Sebla B.; Li, Meiling; Brewer, Gary; Tolbert, Blanton S.; Hargrove, Amanda E.

doi:10.1126/sciadv.abl6096

Cited by 40 publications

(46 citation statements)

References 58 publications

(83 reference statements)

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“…Another amiloride was discovered that inhibits viral replication of the Betacornoavirus OC43 and SARS-CoV-2 (ref. 181 ). A panel of 23 amilorides was screened for inhibition of the infectivity of OC43, affording three lead molecules.…”

Section: Examples Of Small-molecule Rna Bindersmentioning

confidence: 99%

Targeting RNA structures with small molecules

Childs‐Disney

Yang

Gibaut

et al. 2022

Nat Rev Drug Discov

261

219

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RNA adopts 3D structures that confer varied functional roles in human biology and dysfunction in disease. Approaches to therapeutically target RNA structures with small molecules are being actively pursued, aided by key advances in the field including the development of computational tools that predict evolutionarily conserved RNA structures, as well as strategies that expand mode of action and facilitate interactions with cellular machinery. Existing RNA-targeted small molecules use a range of mechanisms including directing splicing — by acting as molecular glues with cellular proteins (such as branaplam and the FDA-approved risdiplam), inhibition of translation of undruggable proteins and deactivation of functional structures in noncoding RNAs. Here, we describe strategies to identify, validate and optimize small molecules that target the functional transcriptome, laying out a roadmap to advance these agents into the next decade.

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Section: Examples Of Small-molecule Rna Bindersmentioning

confidence: 99%

Targeting RNA structures with small molecules

Childs‐Disney

Yang

Gibaut

et al. 2022

Nat Rev Drug Discov

261

219

View full text Add to dashboard Cite

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Section: Viral Rna-targeting Strategiesmentioning

confidence: 99%

“…Amiloride analogs (e.g., DMA-155, Figure 4 ) targeting the SARS-CoV-2 5’ UTR also exhibited antiviral activity in SARS-CoV-2-infected cells ( Zafferani et al, 2020 ). NMR studies uncovered that SL4, SL5a, and SL6 could all bind to the amilorides ( Zafferani et al, 2020 ). An RNA sequence (RG-1) having a high propensity to form a G-quadruplex (G4) in the SARS-CoV-2 genome was validated in the coding sequence of nucleocapsid phosphoprotein (N) in cells ( Zhao et al, 2021 ).…”

Section: Viral Rna-targeting Strategiesmentioning

confidence: 99%

Inhibition of SARS-CoV-2 by Targeting Conserved Viral RNA Structures and Sequences

2021

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The ongoing COVID-19/Severe Acute Respiratory Syndrome CoV-2 (SARS-CoV-2) pandemic has become a significant threat to public health and has hugely impacted societies globally. Targeting conserved SARS-CoV-2 RNA structures and sequences essential for viral genome translation is a novel approach to inhibit viral infection and progression. This new pharmacological modality compasses two classes of RNA-targeting molecules: 1) synthetic small molecules that recognize secondary or tertiary RNA structures and 2) antisense oligonucleotides (ASOs) that recognize the RNA primary sequence. These molecules can also serve as a “bait” fragment in RNA degrading chimeras to eliminate the viral RNA genome. This new type of chimeric RNA degrader is recently named ribonuclease targeting chimera or RIBOTAC. This review paper summarizes the sequence conservation in SARS-CoV-2 and the current development of RNA-targeting molecules to combat this virus. These RNA-binding molecules will also serve as an emerging class of antiviral drug candidates that might pivot to address future viral outbreaks.

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“…We are confident that these resources can expedite structure-guided rational design of small molecules and aid the exploration of novel RNA targets, including those recently identified in SARS-CoV-2. 24,41,42 Future R-BIND updates and the concurrent increase in RNA structural information will enable synergistic insights that will propel the RNA targeting field to new heights. Methods Cheminformatics calculations.…”

Section: Discussionmentioning

confidence: 99%

R-BIND 2.0: An Updated Database of Bioactive RNA-Targeting Small Molecules and Associated RNA Secondary Structures

Donlic

Swanson

Chiu

et al. 2022

Preprint

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Discoveries of RNA roles in cellular physiology and pathology are raising the need for new tools that modulate the structure and function of these biomolecules, and small molecules are proving useful. In 2017, we curated the RNA-targeted BIoactive ligaNd Database (R-BIND) and discovered distinguishing physicochemical properties of RNA-targeting ligands, leading us to propose the existence of an RNA-privileged chemical space. Biennial updates of the database and the establishment of a website platform (rbind.chem.duke.edu) have provided new insights and tools to design small molecules based on the analyzed physicochemical and spatial properties. In this report and R-BIND 2.0 update, we refined the curation approach and ligand classification system as well as conducted analyses of RNA structure elements for the first time to identify new targeting strategies. Specifically, we curated and analyzed RNA target structural motifs to determine properties of small molecules that may confer selectivity for distinct RNA secondary and tertiary structures. Additionally, we collected sequences of target structures and incorporated an RNA Structure Search algorithm into the website that outputs small molecules targeting similar motifs without a priori secondary structure knowledge. Cheminformatic analyses revealed that, despite the 50% increase in small molecule library size, the distinguishing properties of R-BIND ligands remained significantly different to that of proteins and are therefore still relevant to RNA-targeted probe discovery. Combined, we expect these novel insights and website features to enable rational design of RNA-targeted ligands and to serve as a resource and inspiration for a variety of scientists interested in RNA targeting.

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Amilorides inhibit SARS-CoV-2 replication in vitro by targeting RNA structures

Abstract: Small-molecule targeting of RNA stem loops in 5′-end of SARS-CoV-2 reveals novel RNA targets for viral inhibition.

Cited by 40 publications

References 58 publications

Targeting RNA structures with small molecules

Targeting RNA structures with small molecules

Inhibition of SARS-CoV-2 by Targeting Conserved Viral RNA Structures and Sequences

R-BIND 2.0: An Updated Database of Bioactive RNA-Targeting Small Molecules and Associated RNA Secondary Structures

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