Show simple item record

dc.contributor.authorJiang, Li
dc.contributor.authorLiu, Ping
dc.contributor.authorBank, Claudia
dc.contributor.authorRenzette, Nicholas
dc.contributor.authorPrachanronarong, Kristina L.
dc.contributor.authorYilmaz, L. Safak
dc.contributor.authorCaffrey, Daniel R.
dc.contributor.authorZeldovich, Konstantin B.
dc.contributor.authorSchiffer, Celia A.
dc.contributor.authorKowalik, Timothy F.
dc.contributor.authorJensen, Jeffrey D.
dc.contributor.authorFinberg, Robert W.
dc.contributor.authorWang, Jennifer P.
dc.contributor.authorBolon, Daniel N.
dc.date2022-08-11T08:10:52.000
dc.date.accessioned2022-08-23T17:23:05Z
dc.date.available2022-08-23T17:23:05Z
dc.date.issued2016-02-13
dc.date.submitted2016-01-25
dc.identifier.citationJ Mol Biol. 2016 Feb 13;428(3):538-53. doi: 10.1016/j.jmb.2015.11.027. Epub 2015 Dec 4. <a href="http://dx.doi.org/10.1016/j.jmb.2015.11.027">Link to article on publisher's site</a>
dc.identifier.issn0022-2836 (Linking)
dc.identifier.doi10.1016/j.jmb.2015.11.027
dc.identifier.pmid26656922
dc.identifier.urihttp://hdl.handle.net/20.500.14038/48884
dc.description.abstractThe therapeutic benefits of the neuraminidase (NA) inhibitor oseltamivir are dampened by the emergence of drug resistance mutations in influenza A virus (IAV). To investigate the mechanistic features that underlie resistance, we developed an approach to quantify the effects of all possible single-nucleotide substitutions introduced into important regions of NA. We determined the experimental fitness effects of 450 nucleotide mutations encoding positions both surrounding the active site and at more distant sites in an N1 strain of IAV in the presence and absence of oseltamivir. NA mutations previously known to confer oseltamivir resistance in N1 strains, including H275Y and N295S, were adaptive in the presence of drug, indicating that our experimental system captured salient features of real-world selection pressures acting on NA. We identified mutations, including several at position 223, that reduce the apparent affinity for oseltamivir in vitro. Position 223 of NA is located adjacent to a hydrophobic portion of oseltamivir that is chemically distinct from the substrate, making it a hotspot for substitutions that preferentially impact drug binding relative to substrate processing. Furthermore, two NA mutations, K221N and Y276F, each reduce susceptibility to oseltamivir by increasing NA activity without altering drug binding. These results indicate that competitive expansion of IAV in the face of drug pressure is mediated by a balance between inhibitor binding and substrate processing.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=26656922&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1016/j.jmb.2015.11.027
dc.subjectadaptive
dc.subjectexperimental fitness
dc.subjectneuraminidase inhibitor
dc.subjectoseltamivir
dc.subjectsystematic mutation
dc.subjectBiochemistry
dc.subjectImmunity
dc.subjectImmunology of Infectious Disease
dc.subjectImmunoprophylaxis and Therapy
dc.subjectMedicinal Chemistry and Pharmaceutics
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.subjectMolecular Biology
dc.subjectStructural Biology
dc.subjectVirology
dc.titleA Balance between Inhibitor Binding and Substrate Processing Confers Influenza Drug Resistance
dc.typeArticle
dc.source.journaltitleJournal of molecular biology
dc.source.volume428
dc.source.issue3
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/schiffer/3
dc.identifier.contextkey8044963
html.description.abstract<p>The therapeutic benefits of the neuraminidase (NA) inhibitor oseltamivir are dampened by the emergence of drug resistance mutations in influenza A virus (IAV). To investigate the mechanistic features that underlie resistance, we developed an approach to quantify the effects of all possible single-nucleotide substitutions introduced into important regions of NA. We determined the experimental fitness effects of 450 nucleotide mutations encoding positions both surrounding the active site and at more distant sites in an N1 strain of IAV in the presence and absence of oseltamivir. NA mutations previously known to confer oseltamivir resistance in N1 strains, including H275Y and N295S, were adaptive in the presence of drug, indicating that our experimental system captured salient features of real-world selection pressures acting on NA. We identified mutations, including several at position 223, that reduce the apparent affinity for oseltamivir in vitro. Position 223 of NA is located adjacent to a hydrophobic portion of oseltamivir that is chemically distinct from the substrate, making it a hotspot for substitutions that preferentially impact drug binding relative to substrate processing. Furthermore, two NA mutations, K221N and Y276F, each reduce susceptibility to oseltamivir by increasing NA activity without altering drug binding. These results indicate that competitive expansion of IAV in the face of drug pressure is mediated by a balance between inhibitor binding and substrate processing.</p>
dc.identifier.submissionpathschiffer/3
dc.contributor.departmentProgram in Bioinformatics and Integrative Biology
dc.contributor.departmentDepartment of Microbiology and Physiological Systems
dc.contributor.departmentDepartment of Medicine, Division of Infectious Diseases and Immunology
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.source.pages538-53


Files in this item

Thumbnail
Name:
Publisher version

This item appears in the following Collection(s)

Show simple item record