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Bioorg Med Chem. 2014 Sep 1;22(17):4836-47. doi: 10.1016/j.bmc.2014.06.053. Epub 2014 Jul 10.

Structural optimization of a retrograde trafficking inhibitor that protects cells from infections by human polyoma- and papillomaviruses.

Author information

1
Department of Chemistry, Brown University, 324 Brook Street, Providence, RI 02912, United States.
2
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, 185 Meeting Street, Providence, RI 02912, United States.
3
Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, United States.
4
Department of Chemistry, Brown University, 324 Brook Street, Providence, RI 02912, United States. Electronic address: jason_sello@brown.edu.

Abstract

Human polyoma- and papillomaviruses are non-enveloped DNA viruses that cause severe pathologies and mortalities. Under circumstances of immunosuppression, JC polyomavirus causes a fatal demyelinating disease called progressive multifocal leukoencephalopathy (PML) and the BK polyomavirus is the etiological agent of polyomavirus-induced nephropathy and hemorrhagic cystitis. Human papillomavirus type 16, another non-enveloped DNA virus, is associated with the development of cancers in tissues like the uterine cervix and oropharynx. Currently, there are no approved drugs or vaccines to treat or prevent polyomavirus infections. We recently discovered that the small molecule Retro-2(cycl), an inhibitor of host retrograde trafficking, blocked infection by several human and monkey polyomaviruses. Here, we report diversity-oriented syntheses of Retro-2(cycl) and evaluation of the resulting analogs using an assay of human cell infections by JC polyomavirus. We defined structure-activity relationships and also discovered analogs with significantly improved potency as suppressors of human polyoma- and papillomavirus infection in vitro. Our findings represent an advance in the development of drug candidates that can broadly protect humans from non-enveloped DNA viruses and toxins that exploit retrograde trafficking as a means for cell entry.

KEYWORDS:

Dihydroquinazolinone; Papillomavirus; Polyomavirus; Retrograde trafficking; SAR

PMID:
25087050
PMCID:
PMC4378546
DOI:
10.1016/j.bmc.2014.06.053
[Indexed for MEDLINE]
Free PMC Article

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