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AuthorFeldmann, Svenjadc.contributor.author
AuthorGrimm, Immanueldc.contributor.author
AuthorStöhr, Dagmardc.contributor.author
AuthorAntonini, Chiaradc.contributor.author
AuthorLischka, Peterdc.contributor.author
AuthorSinzger, Christiandc.contributor.author
AuthorStegmann, Coradc.contributor.author
Date of accession2021-05-27T07:53:24Zdc.date.accessioned
Available in OPARU since2021-05-27T07:53:24Zdc.date.available
Date of first publication2021-03-29dc.date.issued
AbstractPlatelet-derived growth factor receptor alpha (PDGFRα) serves as an entry receptor for the human cytomegalovirus (HCMV), and soluble PDGFRα-Fc can neutralize HCMV at a halfmaximal effective concentration (EC50) of about 10 ng/ml. While this indicates a potential for usage as an HCMV entry inhibitor PDGFRα-Fc can also bind the physiological ligands of PDGFRα (PDGFs), which likely interferes with the respective signaling pathways and represents a potential source of side effects. Therefore, we tested the hypothesis that interference with PDGF signaling can be prevented by mutations in PDGFRα-Fc or combinations thereof, without losing the inhibitory potential for HCMV. To this aim, a targeted mutagenesis approach was chosen. The mutations were quantitatively tested in biological assays for interference with PDGF-dependent signaling as well as inhibition of HCMV infection and biochemically for reduced affinity to PDGF-BB, facilitating quantification of PDGFRα-Fc selectivity for HCMV inhibition. Mutation of Ile 139 to Glu and Tyr 206 to Ser strongly reduced the affinity for PDGF-BB and hence interference with PDGF-dependent signaling. Inhibition of HCMV infection was less affected, thus increasing the selectivity by factor 4 and 8, respectively. Surprisingly, the combination of these mutations had an additive effect on binding of PDGF-BB but not on inhibition of HCMV, resulting in a synergistic 260fold increase of selectivity. In addition, a recently reported mutation, Val 242 to Lys, was included in the analysis. PDGFRα-Fc with this mutation was fully effective at blocking HCMV entry and had a drastically reduced affinity for PDGF-BB. Combining Val 242 to Lys with Ile 139 to Glu and/or Tyr 206 to Ser further reduced PDGF ligand binding beyond detection. In conclusion, this targeted mutagenesis approach identified combinations of mutations in PDGFRα-Fc that prevent interference with PDGF-BB but maintain inhibition of HCMV, which qualifies such mutants as candidates for the development of HCMV entry inhibitors.dc.description.abstract
Languageendc.language.iso
PublisherUniversität Ulmdc.publisher
LicenseCC BY 4.0 Internationaldc.rights
Link to license texthttps://creativecommons.org/licenses/by/4.0/dc.rights.uri
KeywordSignal inhibitiondc.subject
KeywordEnzyme-linked immunoassaysdc.subject
KeywordGrowth factordc.subject
Dewey Decimal GroupDDC 570 / Life sciencesdc.subject.ddc
Dewey Decimal GroupDDC 610 / Medicine & healthdc.subject.ddc
LCSHGrowth factorsdc.subject.lcsh
MeSHSignal Transductiondc.subject.mesh
MeSHFibroblastsdc.subject.mesh
MeSHNeural Inhibitiondc.subject.mesh
MeSHAlaninedc.subject.mesh
MeSHEndothelial Cellsdc.subject.mesh
MeSHImmunoblottingdc.subject.mesh
MeSHIntercellular Signaling Peptides and Proteinsdc.subject.mesh
TitleTargeted mutagenesis on PDGFRα-Fc identifies amino acid modifications that allow efficient inhibition of HCMV infection while abolishing PDGF sequestrationdc.title
Resource typeWissenschaftlicher Artikeldc.type
VersionpublishedVersiondc.description.version
DOIhttp://dx.doi.org/10.18725/OPARU-37681dc.identifier.doi
URNhttp://nbn-resolving.de/urn:nbn:de:bsz:289-oparu-37743-3dc.identifier.urn
GNDFibroblastdc.subject.gnd
GNDAlanindc.subject.gnd
GNDImmunoblotdc.subject.gnd
GNDFibroblastenwachstumsfaktordc.subject.gnd
InstitutionUKU. Institut für Virologieuulm.affiliationSpecific
Peer reviewjauulm.peerReview
DCMI TypeTextuulm.typeDCMI
CategoryPublikationenuulm.category
In cooperation withAiCuris Anti-infective Cures GmbHuulm.cooperation
In cooperation withUniversità di Padovauulm.cooperation
DOI of original publication10.1371/journal.ppat.1009471dc.relation1.doi
Source - Title of sourcePLoS Pathogenssource.title
Source - Place of publicationPublic Library of Sciencesource.publisher
Source - Volume17source.volume
Source - Issue3source.issue
Source - Year2021source.year
Source - Article numbere1009471source.articleNumber
Source - ISSN1553-7366source.identifier.issn
Source - eISSN1553-7374source.identifier.eissn
Bibliographyuulmuulm.bibliographie
Is Supplemented Byhttps://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009471#sec022dc.relation.isSupplementedBy
Project uulmIGradU / International Graduate School der Universität Ulmuulm.projectOther
xmlui.metadata.uulm.OAfundingOpen-Access-Förderung durch die Medizinische Fakultät der Universität Ulmuulm.OAfunding


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