Targeting of Kaposi’s sarcoma-associated herpesvirus by immunotoxins directed against the viral G protein-coupled receptor, ORF74
Rattachement africain : dk, pl, us, no, cz. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
BACKGROUND AND PURPOSE: Kaposi's sarcoma-associated herpesvirus (KSHV) is a common virus with severe outcome and no effective antiviral treatment. KSHV encodes the constitutive active chemokine receptor ORF74 with broad-spectrum CXC-chemokine binding. Here, we leverage ORF74's mimic of endogenous receptors to design chemokine-based immunotoxins for selective killing of KSHV-infected cells. EXPERIMENTAL APPROACH: Four CXC-chemokines with high affinity to ORF74 were fused to domain II, IB, and III of Pseudomonas exotoxin A to generate fusion toxin proteins (FTPs). FTP-induced cell killing was tested in cells expressing ORF74 or one of four chemokine receptors (CXCR1-4). Internalization of all receptors was probed using SNAP-tagged receptors. Second-generation FTPs were designed from receptor structures and molecular modelling to increase selectivity for ORF74 over CXCR1-4. Finally, antiviral activity of FTPs was tested using genetically engineered KSHV. KEY RESULTS: FTPs, based on the agonists (CXCL1, and -8) and inverse agonists (CXCL10 and -12) of ORF74 potently killed ORF74-expressing cells. The inverse agonist based FTPs leveraged constitutive internalization for efficient toxin delivery via ORF74, whereas agonists increased internalization further. CXCL10-FTP had the strongest cell-killing and, as the only FTP, selectivity for ORF74 over its endogenous receptor, CXCR3. Second-generation FTPs improved this selectivity from 25-fold to 126-fold by the mutation (R8D) in CXCL10-FTP, designed to lose ionic interaction within CXCR3's main binding pocket. Both inverse agonist-based FTPs effectively prevented KSHV-reactivation. CONCLUSION AND IMPLICATIONS: Our findings highlight the versatility of FTPs in precise delivery of toxin payloads and provide a foundation for potential applications in antiviral and anticancer therapies targeting KSHV-associated diseases.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Targeting of Kaposi’s sarcoma-associated herpesvirus by immunotoxins directed against the viral G protein-coupled receptor, ORF74
- Date Crossref
- 01/02/2026
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of Copenhagen Department of Biomedical Sciences pays non établi dans la noticeUniversité ou école supérieure
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Lodz University of Technology pays non établi dans la noticeUniversité ou école supérieure
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University of Łódź pays non établi dans la noticeUniversité ou école supérieure
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University of Washington Department of Microbiology pays non établi dans la noticeUniversité ou école supérieure
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Nordland Hospital Trust pays non établi dans la noticeÉtablissement de santé
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Synlab Czech (Czechia) pays non établi dans la noticeEntreprise
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Helgeland Hospital Trust pays non établi dans la noticeÉtablissement de santé
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Institute of Integrated Research Advanced Research Initiative pays non établi dans la noticeStructure de recherche
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Synklino A/S pays non établi dans la noticeInstitution
Department of Biomedical Sciences — University of Copenhagen, Lodz University of Technology et University of Łódź, avec 6 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.