JC virus (JCV] is a common human polyomavirus that infects over 70% of the population worldwide. JCV has a restricted cell tropism that is partly due to the initial interaction between the virus and sialic acid containing host cell receptors. We have identified the molecular determinants for interaction between the virus and its cellular receptor, using a combined approach of site-directed mutagenesis and homology-based molecular modeling. Here, we propose incorporating the JCV sialic acid binding domain onto 4-helix bundle proteins, providing a soluble platform for in-depth biophysical characterization of the virus/sialic acid association as well as screening of compounds for potent inhibitors. Preliminary results indicate that the protein platform is a potent inhibitor of JC viral infection and competes with the virus for cell surface receptors. We propose to further characterize the protein template, including comparing the results from mutagenesis studies to those previously carried out for the intact virus. Initial structural studies, employing circular dichroism and highresolution NMR of 15N and 13C enriched samples, display a stable, folded protein and the expected sialic acid binding profile. The structure of the protein template while associated with sialic acid will be determined by NMR, providing the insight for rational design of inhibitors for the association of JCV with its host cell. The JCV templates will also be developed for screening of small compound libraries. Molecules produced from these efforts will allow us to further probe the pathogenesis of JCV induced disease and may lead to novel therapies

Public Health Relevance

The JC virus is the etiological agent for PML, a fatal complication for immunosuppressed individuals, most notably AIDS patients. Here, we propose the characterization of the initial interaction of the JC virus with the host cell employing a model protein system to mimic the JC viral coat, with the aim of developing molecular inhibitors thay may provide a novel route for therapy development

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS065719-05
Application #
8512817
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$258,027
Indirect Cost
Name
Brown University
Department
Type
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
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Haley, Sheila A; Atwood, Walter J (2017) Progressive Multifocal Leukoencephalopathy: Endemic Viruses and Lethal Brain Disease. Annu Rev Virol 4:349-367
Assetta, Benedetta; Atwood, Walter J (2017) The biology of JC polyomavirus. Biol Chem 398:839-855
Dietrich, Melanie H; Harprecht, Christina; Stehle, Thilo (2017) The bulky and the sweet: How neutralizing antibodies and glycan receptors compete for virus binding. Protein Sci 26:2342-2354
Dimitriadi, Maria; Derdowski, Aaron; Kalloo, Geetika et al. (2016) Decreased function of survival motor neuron protein impairs endocytic pathways. Proc Natl Acad Sci U S A 113:E4377-86
Assetta, Benedetta; De Cecco, Marco; O'Hara, Bethany et al. (2016) JC Polyomavirus Infection of Primary Human Renal Epithelial Cells Is Controlled by a Type I IFN-Induced Response. MBio 7:
Luo, Yong; Motamedi, Nasim; Magaldi, Thomas G et al. (2016) Interaction between Simian Virus 40 Major Capsid Protein VP1 and Cell Surface Ganglioside GM1 Triggers Vacuole Formation. MBio 7:e00297
Jelcic, Ivan; Combaluzier, Benoit; Jelcic, Ilijas et al. (2015) Broadly neutralizing human monoclonal JC polyomavirus VP1-specific antibodies as candidate therapeutics for progressive multifocal leukoencephalopathy. Sci Transl Med 7:306ra150
Haley, Sheila A; O'Hara, Bethany A; Nelson, Christian D S et al. (2015) Human polyomavirus receptor distribution in brain parenchyma contrasts with receptor distribution in kidney and choroid plexus. Am J Pathol 185:2246-58
Ströh, Luisa J; Maginnis, Melissa S; Blaum, Bärbel S et al. (2015) The Greater Affinity of JC Polyomavirus Capsid for ?2,6-Linked Lactoseries Tetrasaccharide c than for Other Sialylated Glycans Is a Major Determinant of Infectivity. J Virol 89:6364-75

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