{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T11:54:28Z","timestamp":1767182068638,"version":"build-2238731810"},"update-to":[{"DOI":"10.1371\/journal.ppat.1009471","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,4,8]],"date-time":"2021-04-08T00:00:00Z","timestamp":1617840000000}}],"reference-count":84,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T00:00:00Z","timestamp":1616976000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008672","name":"Wilhelm Sander-Stiftung","doi-asserted-by":"publisher","award":["2013.002.2"],"award-info":[{"award-number":["2013.002.2"]}],"id":[{"id":"10.13039\/100008672","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008672","name":"Wilhelm Sander-Stiftung","doi-asserted-by":"publisher","award":["2019.029.1"],"award-info":[{"award-number":["2019.029.1"]}],"id":[{"id":"10.13039\/100008672","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019218","name":"International Graduate School in Molecular Medicine","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100019218","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Platelet-derived growth factor receptor alpha (PDGFR\u03b1) serves as an entry receptor for the human cytomegalovirus (HCMV), and soluble PDGFR\u03b1-Fc can neutralize HCMV at a half-maximal effective concentration (EC50) of about 10 ng\/ml. While this indicates a potential for usage as an HCMV entry inhibitor PDGFR\u03b1-Fc can also bind the physiological ligands of PDGFR\u03b1 (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 PDGFR\u03b1-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 PDGFR\u03b1-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. PDGFR\u03b1-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 PDGFR\u03b1-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.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009471","type":"journal-article","created":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T13:37:51Z","timestamp":1617025071000},"page":"e1009471","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Targeted mutagenesis on PDGFR\u03b1-Fc identifies amino acid modifications that allow efficient inhibition of HCMV infection while abolishing PDGF sequestration"],"prefix":"10.1371","volume":"17","author":[{"given":"Svenja","family":"Feldmann","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Immanuel","family":"Grimm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dagmar","family":"St\u00f6hr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3993-3516","authenticated-orcid":true,"given":"Chiara","family":"Antonini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Lischka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9282-1783","authenticated-orcid":true,"given":"Christian","family":"Sinzger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4408-4026","authenticated-orcid":true,"given":"Cora","family":"Stegmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,3,29]]},"reference":[{"key":"ppat.1009471.ref001","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1002\/rmv.655","article-title":"Review 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