Drug Repurposing Identifies Inhibitors of Oseltamivir‐Resistant Influenza Viruses
Identifieur interne : 001163 ( Istex/Corpus ); précédent : 001162; suivant : 001164Drug Repurposing Identifies Inhibitors of Oseltamivir‐Resistant Influenza Viruses
Auteurs : Ju Bao ; Bindumadhav Marathe ; Elena A. Govorkova ; Jie J. ZhengSource :
- Angewandte Chemie International Edition [ 1433-7851 ] ; 2016-03-01.
Abstract
The neuraminidase (NA) inhibitor, oseltamivir, is a widely used anti‐influenza drug. However, oseltamivir‐resistant H1N1 influenza viruses carrying the H275Y NA mutation spontaneously emerged as a result of natural genetic drift and drug treatment. Because H275Y and other potential mutations may generate a future pandemic influenza strain that is oseltamivir‐resistant, alternative therapy options are needed. Herein, we show that a structure‐based computational method can be used to identify existing drugs that inhibit resistant viruses, thereby providing a first line of pharmaceutical defense against this possible scenario. We identified two drugs, nalidixic acid and dorzolamide, that potently inhibit the NA activity of oseltamivir‐resistant H1N1 viruses with the H275Y NA mutation at very low concentrations, but have no effect on wild‐type H1N1 NA even at a much higher concentration, suggesting that the oseltamivir‐resistance mutation itself caused susceptibility to these drugs.
Finding a new purpose: A structure‐based computational screen identified the FDA‐approved drugs nalidixic acid and dorzolamide as potent inhibitors of the influenza H275Y neuraminidase mutant, but not the wild‐type enzyme. H275Y is the most common drug‐resistance mutation in neuraminidase, and this screening method enables rapid identification of inhibitors for newly emerging mutations.
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DOI: 10.1002/anie.201511361
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<front><div type="abstract" xml:lang="en">The neuraminidase (NA) inhibitor, oseltamivir, is a widely used anti‐influenza drug. However, oseltamivir‐resistant H1N1 influenza viruses carrying the H275Y NA mutation spontaneously emerged as a result of natural genetic drift and drug treatment. Because H275Y and other potential mutations may generate a future pandemic influenza strain that is oseltamivir‐resistant, alternative therapy options are needed. Herein, we show that a structure‐based computational method can be used to identify existing drugs that inhibit resistant viruses, thereby providing a first line of pharmaceutical defense against this possible scenario. We identified two drugs, nalidixic acid and dorzolamide, that potently inhibit the NA activity of oseltamivir‐resistant H1N1 viruses with the H275Y NA mutation at very low concentrations, but have no effect on wild‐type H1N1 NA even at a much higher concentration, suggesting that the oseltamivir‐resistance mutation itself caused susceptibility to these drugs.</div>
<div type="abstract" xml:lang="en">Finding a new purpose: A structure‐based computational screen identified the FDA‐approved drugs nalidixic acid and dorzolamide as potent inhibitors of the influenza H275Y neuraminidase mutant, but not the wild‐type enzyme. H275Y is the most common drug‐resistance mutation in neuraminidase, and this screening method enables rapid identification of inhibitors for newly emerging mutations.</div>
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<p>The neuraminidase (NA) inhibitor, oseltamivir, is a widely used anti‐influenza drug. However, oseltamivir‐resistant H1N1 influenza viruses carrying the H275Y NA mutation spontaneously emerged as a result of natural genetic drift and drug treatment. Because H275Y and other potential mutations may generate a future pandemic influenza strain that is oseltamivir‐resistant, alternative therapy options are needed. Herein, we show that a structure‐based computational method can be used to identify existing drugs that inhibit resistant viruses, thereby providing a first line of pharmaceutical defense against this possible scenario. We identified two drugs, nalidixic acid and dorzolamide, that potently inhibit the NA activity of oseltamivir‐resistant H1N1 viruses with the H275Y NA mutation at very low concentrations, but have no effect on wild‐type H1N1 NA even at a much higher concentration, suggesting that the oseltamivir‐resistance mutation itself caused susceptibility to these drugs.</p>
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: A structure‐based computational screen identified the FDA‐approved drugs nalidixic acid and dorzolamide as potent inhibitors of the influenza H275Y neuraminidase mutant, but not the wild‐type enzyme. H275Y is the most common drug‐resistance mutation in neuraminidase, and this screening method enables rapid identification of inhibitors for newly emerging mutations.<figure type="box"><media mimeType="image" url="urn:x-wiley:14337851:media:anie201511361:anie201511361-toc-0001"></media>
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<b>2016</b>
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<titleGroup><title type="main" xml:lang="en">Drug Repurposing Identifies Inhibitors of Oseltamivir‐Resistant Influenza Viruses</title>
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<supportingInformation><p>As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.</p>
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<p>The neuraminidase (NA) inhibitor, oseltamivir, is a widely used anti‐influenza drug. However, oseltamivir‐resistant H1N1 influenza viruses carrying the H275Y NA mutation spontaneously emerged as a result of natural genetic drift and drug treatment. Because H275Y and other potential mutations may generate a future pandemic influenza strain that is oseltamivir‐resistant, alternative therapy options are needed. Herein, we show that a structure‐based computational method can be used to identify existing drugs that inhibit resistant viruses, thereby providing a first line of pharmaceutical defense against this possible scenario. We identified two drugs, nalidixic acid and dorzolamide, that potently inhibit the NA activity of oseltamivir‐resistant H1N1 viruses with the H275Y NA mutation at very low concentrations, but have no effect on wild‐type H1N1 NA even at a much higher concentration, suggesting that the oseltamivir‐resistance mutation itself caused susceptibility to these drugs.</p>
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<abstract type="graphical" xml:lang="en"><p><b>Finding a new purpose</b>
: A structure‐based computational screen identified the FDA‐approved drugs nalidixic acid and dorzolamide as potent inhibitors of the influenza H275Y neuraminidase mutant, but not the wild‐type enzyme. H275Y is the most common drug‐resistance mutation in neuraminidase, and this screening method enables rapid identification of inhibitors for newly emerging mutations.<blockFixed type="graphic"><mediaResourceGroup><mediaResource alt="image" href="urn:x-wiley:14337851:media:anie201511361:anie201511361-toc-0001"></mediaResource>
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<abstract lang="en">The neuraminidase (NA) inhibitor, oseltamivir, is a widely used anti‐influenza drug. However, oseltamivir‐resistant H1N1 influenza viruses carrying the H275Y NA mutation spontaneously emerged as a result of natural genetic drift and drug treatment. Because H275Y and other potential mutations may generate a future pandemic influenza strain that is oseltamivir‐resistant, alternative therapy options are needed. Herein, we show that a structure‐based computational method can be used to identify existing drugs that inhibit resistant viruses, thereby providing a first line of pharmaceutical defense against this possible scenario. We identified two drugs, nalidixic acid and dorzolamide, that potently inhibit the NA activity of oseltamivir‐resistant H1N1 viruses with the H275Y NA mutation at very low concentrations, but have no effect on wild‐type H1N1 NA even at a much higher concentration, suggesting that the oseltamivir‐resistance mutation itself caused susceptibility to these drugs.</abstract>
<abstract type="graphical" lang="en">Finding a new purpose: A structure‐based computational screen identified the FDA‐approved drugs nalidixic acid and dorzolamide as potent inhibitors of the influenza H275Y neuraminidase mutant, but not the wild‐type enzyme. H275Y is the most common drug‐resistance mutation in neuraminidase, and this screening method enables rapid identification of inhibitors for newly emerging mutations.</abstract>
<note type="funding">NIH - No. GM100909; No. CA21765; </note>
<note type="funding">NIH - No. HHSN266200700005C; </note>
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