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However, the side effects, low affinity, and poor efficacy of RSK modulators limit their clinical application. In this study, we developed a nontoxic cell-permeable ORF45-derived peptide from the RSK-binding region to disrupt ORF45-RSK associations and block ORF45-induced RSK activation without interfering with S6K1 activation. This peptide effectively suppresses spontaneous, hypoxia-induced, or chemically induced KSHV lytic replication and enhances the inhibitory effect of rapamycin on lytic replication and sensitivity to rapamycin in lytic KSHV-infected cells. Our results reveal that the ORF45-RSK signaling axis and KSHV lytic replication can be effectively targeted by a short peptide and provide a specific approach for treating KSHV lytic and persistent infection.<\/jats:p>","DOI":"10.1128\/jvi.02154-18","type":"journal-article","created":{"date-parts":[[2019,3,6]],"date-time":"2019-03-06T10:26:40Z","timestamp":1551868000000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":11,"title":["Development of an ORF45-Derived Peptide To Inhibit the Sustained RSK Activation and Lytic Replication of Kaposi's Sarcoma-Associated Herpesvirus"],"prefix":"10.1128","volume":"93","author":[{"given":"Xiaojuan","family":"Li","sequence":"first","affiliation":[{"name":"Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 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