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

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Abstract

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

          Abstract

          The SARS-CoV-2 pandemic, and the likelihood of future coronavirus pandemics, emphasized the urgent need for development of novel antivirals. Small-molecule chemical probes offer both to reveal aspects of virus replication and to serve as leads for antiviral therapeutic development. Here, we report on the identification of amiloride-based small molecules that potently inhibit OC43 and SARS-CoV-2 replication through targeting of conserved structured elements within the viral 5′-end. Nuclear magnetic resonance–based structural studies revealed specific amiloride interactions with stem loops containing bulge like structures and were predicted to be strongly bound by the lead amilorides in retrospective docking studies. Amilorides represent the first antiviral small molecules that target RNA structures within the 5′ untranslated regions and proximal region of the CoV genomes. These molecules will serve as chemical probes to further understand CoV RNA biology and can pave the way for the development of specific CoV RNA–targeted antivirals.

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          Most cited references57

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          MAFFT Multiple Sequence Alignment Software Version 7: Improvements in Performance and Usability

          Kazutaka Katoh, Daron Standley (2013)
          We report a major update of the MAFFT multiple sequence alignment program. This version has several new features, including options for adding unaligned sequences into an existing alignment, adjustment of direction in nucleotide alignment, constrained alignment and parallel processing, which were implemented after the previous major update. This report shows actual examples to explain how these features work, alone and in combination. Some examples incorrectly aligned by MAFFT are also shown to clarify its limitations. We discuss how to avoid misalignments, and our ongoing efforts to overcome such limitations.
          Article 0 comments Cited 10431 times – based on 0 reviews     Review now
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            A new coronavirus associated with human respiratory disease in China

            Fan Wu, Su Zhao, Bin Yu … (2020)
            Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health 1–3 . Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019. Epidemiological investigations have suggested that the outbreak was associated with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 December 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing 4 of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here ‘WH-Human 1’ coronavirus (and has also been referred to as ‘2019-nCoV’). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China 5 . This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.
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              Gapped BLAST and PSI-BLAST: a new generation of protein database search programs.

              S Altschul (1997)
              The BLAST programs are widely used tools for searching protein and DNA databases for sequence similarities. For protein comparisons, a variety of definitional, algorithmic and statistical refinements described here permits the execution time of the BLAST programs to be decreased substantially while enhancing their sensitivity to weak similarities. A new criterion for triggering the extension of word hits, combined with a new heuristic for generating gapped alignments, yields a gapped BLAST program that runs at approximately three times the speed of the original. In addition, a method is introduced for automatically combining statistically significant alignments produced by BLAST into a position-specific score matrix, and searching the database using this matrix. The resulting Position-Specific Iterated BLAST (PSI-BLAST) program runs at approximately the same speed per iteration as gapped BLAST, but in many cases is much more sensitive to weak but biologically relevant sequence similarities. PSI-BLAST is used to uncover several new and interesting members of the BRCT superfamily.
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                Author and article information

                Contributors
                Martina Zafferani:
                ORCID: https://orcid.org/0000-0003-4586-1843
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Christina Haddad:
                ORCID: https://orcid.org/0000-0003-4082-2941
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Le Luo:
                ORCID: https://orcid.org/0000-0002-2643-1904
                Role: InvestigationRole: MethodologyRole: Validation
                Jesse Davila-Calderon:
                ORCID: https://orcid.org/0000-0002-9991-4536
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: VisualizationRole: Writing - review & editing
                Liang-Yuan Chiu:
                ORCID: https://orcid.org/0000-0002-0584-1023
                Role: InvestigationRole: Visualization
                Christian Shema Mugisha:
                ORCID: https://orcid.org/0000-0002-0517-7986
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: Validation
                Adeline G. Monaghan: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - review & editing
                Andrew A. Kennedy:
                ORCID: https://orcid.org/0000-0002-3747-0597
                Role: InvestigationRole: MethodologyRole: ValidationRole: Writing - original draft
                Joseph D. Yesselman: Role: ConceptualizationRole: Software
                Robert J. Gifford:
                ORCID: https://orcid.org/0000-0003-4028-9884
                Role: Formal analysisRole: InvestigationRole: VisualizationRole: Writing - original draft
                Andrew W. Tai:
                ORCID: https://orcid.org/0000-0002-6877-450X
                Role: Formal analysisRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - review & editing
                Sebla B. Kutluay:
                ORCID: https://orcid.org/0000-0001-5549-7032
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draft
                Mei-Ling Li:
                ORCID: https://orcid.org/0000-0001-6172-5521
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Gary Brewer:
                ORCID: https://orcid.org/0000-0002-4180-3964
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - review & editing
                Blanton S. Tolbert:
                ORCID: https://orcid.org/0000-0003-2456-0443
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Amanda E. Hargrove:
                ORCID: https://orcid.org/0000-0003-1536-6753
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Journal
                Journal ID (nlm-ta): Sci Adv
                Journal ID (iso-abbrev): Sci Adv
                Journal ID (publisher-id): sciadv
                Journal ID (hwp): advances
                Title: Science Advances
                Publisher: American Association for the Advancement of Science
                ISSN (Electronic): 2375-2548
                Publication date Collection: November 2021
                Publication date (Electronic, pub): 26 November 2021
                Volume: 7
                Issue: 48
                Electronic Location Identifier: eabl6096
                Affiliations
                [1 ]Chemistry Department, Duke University, 124 Science Drive, Durham, NC 27705, USA.
                [2 ]Department of Chemistry, Case Western Reserve University, Cleveland, OH 441106, USA.
                [3 ]Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
                [4 ]Department of Internal Medicine and Department of Microbiology and Immunology, University of Michigan, 1150 W Medical Center Dr., Ann Arbor, MI 48109, USA.
                [5 ]Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.
                [6 ]MRC-University of Glasgow Centre for Virus Research, 464 Bearsden Rd., Bearsden, Glasgow G61 1QH, UK.
                [7 ]Department of Biochemistry and Molecular Biology, Rutgers Robert Wood Johnson Medical School, 675 Hoes Lane West, Piscataway, NJ 08854, USA.
                Author notes
                [†]

                Co-first authors.

                [‡]

                Co-second authors.

                Author information
                https://orcid.org/0000-0003-4586-1843
                https://orcid.org/0000-0003-4082-2941
                https://orcid.org/0000-0002-2643-1904
                https://orcid.org/0000-0002-9991-4536
                https://orcid.org/0000-0002-0584-1023
                https://orcid.org/0000-0002-0517-7986
                https://orcid.org/0000-0002-3747-0597
                https://orcid.org/0000-0003-4028-9884
                https://orcid.org/0000-0002-6877-450X
                https://orcid.org/0000-0001-5549-7032
                https://orcid.org/0000-0001-6172-5521
                https://orcid.org/0000-0002-4180-3964
                https://orcid.org/0000-0003-2456-0443
                https://orcid.org/0000-0003-1536-6753
                Article
                Publisher ID: abl6096
                DOI: 10.1126/sciadv.abl6096
                PMC ID: 8626076
                PubMed ID: 34826236
                SO-VID: 1e07e7c2-5ad7-44be-a1e3-bfb7e03d5c35
                Copyright © Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                Date received : 26 July 2021
                Date accepted : 06 October 2021
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;
                Award ID: R35GM124785
                Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;
                Award ID: GM126833
                Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;
                Award ID: GM126833
                Funded by: FundRef http://dx.doi.org/10.13039/100006510, Duke University;
                Funded by: Medical Research Council of the United Kingdom;
                Award ID: 12014/12
                Funded by: Tobacco Settlement Fund;
                Award ID: 21-5734-0010
                Categories
                Subject: Research Article
                Subject: Biomedicine and Life Sciences
                Subject: SciAdv r-articles
                Subject: Biophysics
                Subject: Virology
                Subject: Coronavirus
                Custom metadata
                Copyeditor Kyle Solis

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