Skip to content

Month: September 2014

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

Published on
Biochemistry. 2014 Sep 23;53(37):5916-22. doi: 10.1021/bi500368k. Epub 2014 Sep 15.

Small Molecule Inhibition of the Na+/H+ Exchange Regulatory Factor 1 and Parathyroid Hormone 1 Receptor Interaction.

Abstract

We have identified a series of small molecules that bind to the canonical peptide binding groove of the PDZ1 domain of NHERF1 and effectively compete with the association of the C-terminus of the parathyroid hormone 1 receptor (PTH1R). Employing nuclear magnetic resonance and molecular modeling, we characterize the mode of binding that involves the GYGF loop important for the association of the C-terminus of PTH1R. We demonstrate that the common core of the small molecules binds to the PDZ1 domain of NHERF1 and displaces a 15N-labeled peptide corresponding to the C-terminus of PTH1R. The small size (molecular weight of 192) of this core scaffold makes it an excellent candidate for further elaboration in the development of an inhibitor for this important protein-protein interaction.

http://www.ncbi.nlm.nih.gov/pubmed/25171053

Small molecule docked to NHERF PDZ
Small molecule docked to NHERF PDZ

Published on
ATP_paper_artChem Commun (Camb). 2014 Sep 16;50(81):12037-9. doi: 10.1039/c4cc04399e.

Monitoring ATP hydrolysis and ATPase inhibitor screening using (1)H NMR.

Abstract

We present a versatile method to characterize ATPase and kinase activities and discover new inhibitors of these proteins. The proton NMR-based assay directly monitors ATP turnover and is easy to implement, requires no additional reagents and can potentially be applied to GTP. We validated the method's accuracy, applied it to the monitoring of ATP turnover by actin and to the screening of ATPase inhibitors, and showed that it is also applicable for the monitoring of GTP hydrolysis.

http://www.ncbi.nlm.nih.gov/pubmed/25170530