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Tag: JCV

Published on
J Pept Sci. 2014 Dec 19. doi: 10.1002/psc.2731. [Epub ahead of print]

Small-molecule inhibitors of JC polyomavirus infection.

Yatawara A1, Gaidos G, Rupasinghe CN, O'Hara BA, Pellegrini M, Atwood WJ, Mierke DF.

Abstract

The JC polyomavirus (JCPyV) infects approximately 50% of the human population. In healthy individuals, the infection remains dormant and asymptomatic, but in immuno-suppressed patients, it can cause progressive multifocal leukoencephalopathy (PML), a potentially fatal demyelinating disease. Currently, there are no drugs against JCPyV infection nor for the treatment of PML. Here, we report the development of small-molecule inhibitors of JCPyV that target the initial interaction between the virus and host cell and thereby block viral entry. Utilizing a combination of computational and NMR-based screening techniques, we target the LSTc tetrasaccharide binding site within the VP1 pentameric coat protein of JCPyV. Four of the compounds from the screen effectively block viral infection in our in vitro assays using SVG-A cells. For the most potent compound, we used saturation transfer difference NMR to determine the mode of binding to purified pentamers of JCPyV VP1. Collectively, these results demonstrate the viability of this class of compounds for eventual development of JCPyV-antiviral therapeutics.

http://www.ncbi.nlm.nih.gov/pubmed/25522925

Published on
Virus Res. 2014 Aug 30;189:280-5. doi: 10.1016/j.virusres.2014.06.008. Epub 2014 Jun 21.

Gallic acid-based small-molecule inhibitors of JC and BK polyomaviral infection.

O'Hara BA1, Rupasinghe C2, Yatawara A2, Gaidos G2, Mierke DF2, Atwood WJ3.

Abstract

JCPyV and BKPyV are common human polyomaviruses that cause lifelong asymptomatic persistent infections in their hosts. In immunosuppressed individuals, increased replication of JCPyV and BKPyV cause significant disease. JCPyV causes a fatal and rapidly progressing demyelinating disease known as progressive multifocal leukoencephalopathy. BKPyV causes hemorrhagic cystitis and polyomavirus associated nephropathy in bone marrow transplant recipients and in renal transplant recipients respectively. There are no specific anti-viral therapies to treat polyomavirus induced diseases. Based on detailed studies of the structures of these viruses bound to their receptors we screened several compounds that possessed similar chemical space as sialic acid for their ability to bind the virus. Positive hits in the assay were restricted to gallic acid based compounds that mimic the viruses known cellular glycan receptors. Pre-treatment of virions with these inhibitors reduced virus infection in cell culture and as such may form the basis for the development of virion specific antagonists to treat these infections.

http://www.ncbi.nlm.nih.gov/pubmed/24960120