Author | Feldmann, Svenja | dc.contributor.author |
Author | Grimm, Immanuel | dc.contributor.author |
Author | Stöhr, Dagmar | dc.contributor.author |
Author | Antonini, Chiara | dc.contributor.author |
Author | Lischka, Peter | dc.contributor.author |
Author | Sinzger, Christian | dc.contributor.author |
Author | Stegmann, Cora | dc.contributor.author |
Date of accession | 2021-05-27T07:53:24Z | dc.date.accessioned |
Available in OPARU since | 2021-05-27T07:53:24Z | dc.date.available |
Date of first publication | 2021-03-29 | dc.date.issued |
Abstract | Platelet-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 |
Language | en | dc.language.iso |
Publisher | Universität Ulm | dc.publisher |
License | CC BY 4.0 International | dc.rights |
Link to license text | https://creativecommons.org/licenses/by/4.0/ | dc.rights.uri |
Keyword | Signal inhibition | dc.subject |
Keyword | Enzyme-linked immunoassays | dc.subject |
Keyword | Growth factor | dc.subject |
Dewey Decimal Group | DDC 570 / Life sciences | dc.subject.ddc |
Dewey Decimal Group | DDC 610 / Medicine & health | dc.subject.ddc |
LCSH | Growth factors | dc.subject.lcsh |
MeSH | Signal Transduction | dc.subject.mesh |
MeSH | Fibroblasts | dc.subject.mesh |
MeSH | Neural Inhibition | dc.subject.mesh |
MeSH | Alanine | dc.subject.mesh |
MeSH | Endothelial Cells | dc.subject.mesh |
MeSH | Immunoblotting | dc.subject.mesh |
MeSH | Intercellular Signaling Peptides and Proteins | dc.subject.mesh |
Title | Targeted mutagenesis on PDGFRα-Fc identifies amino acid modifications that allow efficient inhibition of HCMV infection while
abolishing PDGF sequestration | dc.title |
Resource type | Wissenschaftlicher Artikel | dc.type |
Version | publishedVersion | dc.description.version |
DOI | http://dx.doi.org/10.18725/OPARU-37681 | dc.identifier.doi |
URN | http://nbn-resolving.de/urn:nbn:de:bsz:289-oparu-37743-3 | dc.identifier.urn |
GND | Fibroblast | dc.subject.gnd |
GND | Alanin | dc.subject.gnd |
GND | Immunoblot | dc.subject.gnd |
GND | Fibroblastenwachstumsfaktor | dc.subject.gnd |
Institution | UKU. Institut für Virologie | uulm.affiliationSpecific |
Peer review | ja | uulm.peerReview |
DCMI Type | Text | uulm.typeDCMI |
Category | Publikationen | uulm.category |
In cooperation with | AiCuris Anti-infective Cures GmbH | uulm.cooperation |
In cooperation with | Università di Padova | uulm.cooperation |
DOI of original publication | 10.1371/journal.ppat.1009471 | dc.relation1.doi |
Source - Title of source | PLoS Pathogens | source.title |
Source - Place of publication | Public Library of Science | source.publisher |
Source - Volume | 17 | source.volume |
Source - Issue | 3 | source.issue |
Source - Year | 2021 | source.year |
Source - Article number | e1009471 | source.articleNumber |
Source - ISSN | 1553-7366 | source.identifier.issn |
Source - eISSN | 1553-7374 | source.identifier.eissn |
Bibliography | uulm | uulm.bibliographie |
Is Supplemented By | https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009471#sec022 | dc.relation.isSupplementedBy |
Project uulm | IGradU / International Graduate School der Universität Ulm | uulm.projectOther |
xmlui.metadata.uulm.OAfunding | Open-Access-Förderung durch die Medizinische Fakultät der Universität Ulm | uulm.OAfunding |