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Proven HPyV diseases with documented histopathology affect primarily immunocompromised hosts with manifestations in brain, skin and renourinary tract such as polyomavirus\u2010associated nephropathy (PyVAN), polyomavirus\u2010associated haemorrhagic cystitis (PyVHC), polyomavirus\u2010associated urothelial cancer (PyVUC), progressive multifocal leukoencephalopathy (PML), Merkel cell carcinoma (MCC),<jats:italic>Trichodysplasia spinulosa<\/jats:italic>(TS) and pruritic hyperproliferative keratinopathy. Although virus\u2010specific immune control is the eventual goal of therapy and lasting cure, antiviral treatments are urgently needed in order to reduce or prevent HPyV diseases and thereby bridging the time needed to establish virus\u2010specific immunity. However, the small dsDNA genome of only 5\u00a0kb of the non\u2010enveloped HPyVs only encodes 5\u20137 viral proteins. Thus, HPyV replication relies heavily on host cell factors, thereby limiting both, number and type of specific virus\u2010encoded antiviral targets. Lack of cost\u2010effective high\u2010throughput screening systems and relevant small animal models complicates the preclinical development. Current clinical studies are limited by small case numbers, poorly efficacious compounds and absence of proper randomized trial design. Here, we review preclinical and clinical studies that evaluated small molecules with presumed antiviral activity against HPyVs and provide an outlook regarding potential new antiviral strategies.<\/jats:p>","DOI":"10.1002\/rmv.2220","type":"journal-article","created":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T12:55:08Z","timestamp":1615985708000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Antivirals against human polyomaviruses: Leaving no stone unturned"],"prefix":"10.1002","volume":"31","author":[{"given":"Zongsong","family":"Wu","sequence":"first","affiliation":[{"name":"Transplantation &amp; Clinical Virology, Department Biomedicine University of Basel Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1132-5348","authenticated-orcid":false,"given":"Fabrice 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