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

AI Article Synopsis

  • Human polyoma- and papillomaviruses are non-enveloped DNA viruses that can lead to severe health issues, including fatal diseases like progressive multifocal leukoencephalopathy and certain cancers.
  • There are currently no approved treatments or vaccines for infections caused by these viruses, highlighting a critical need for effective solutions.
  • Recent research discovered a molecule (Retro-2(cycl)) that can inhibit these viruses; further analysis has led to more potent analogs that show promise in blocking infections in human cells.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378546PMC
http://dx.doi.org/10.1016/j.bmc.2014.06.053DOI Listing

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