Core B will provide materials and carry out functions essential for Projects 1-3 of this Program Project. The functions include the synthesis of peptides, peptidomimetics, as well as natural and modified gangliosides that are required for the investigations described in the individual projects. These materials will be used for cocrystallization structural studies and in the biological function and biochemical screening assays detailed here. In addition, the core will provide labeled (e.g., fluorescently tagged) saccharides/gangliosides for biochemical and functional assays necessary to probe the mechanism of action of the molecular inhibitors developed in this Program Project. Peptide domains of the serotonin 5HT2a receptor will be synthesized as part of Project #2, to investigate the development of inhibitors of the initial association for viral entry. Within the core, small well focused peptide and peptidomimetic libraries will be synthesized for the screening assays detailed in Project #3. The hits identified from these screening efforts will be scaled up within the Core for functional characterization with respect to viral infection (Project #2) and co-crystallization studies with the VPl protein (Project #1). Using the latest techniques for the preparative purification of peptides and gangliosides, we will provide 1 to 100mg of highly purified material to support investigations carried out in the Projects. All of the materials will be extensively characterized by the techniques available to the Core, including MS, HPLC, and NMR. These techniques plus CD, fluorescence, FPLC, ITC, and dynamic light scattering are available within the Core for indepth analytical characterization of peptides/proteins generated within the individual projects. The Core provides both state-of-the-art instrumentation and highly trained investigators and support personnel to carry out these research efforts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS065719-05
Application #
8512821
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
$195,013
Indirect Cost
Name
Brown University
Department
Type
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Maginnis, Melissa S; Nelson, Christian D S; Atwood, Walter J (2015) JC polyomavirus attachment, entry, and trafficking: unlocking the keys to a fatal infection. J Neurovirol 21:601-13
Zins, Stephen R; Nelson, Christian D S; Maginnis, Melissa S et al. (2014) The human alpha defensin HD5 neutralizes JC polyomavirus infection by reducing endoplasmic reticulum traffic and stabilizing the viral capsid. J Virol 88:948-60
O'Hara, Bethany A; Rupasinghe, Chamila; Yatawara, Achani et al. (2014) Gallic acid-based small-molecule inhibitors of JC and BK polyomaviral infection. Virus Res 189:280-5
Carney, Daniel W; Nelson, Christian D S; Ferris, Bennett D et al. (2014) Structural optimization of a retrograde trafficking inhibitor that protects cells from infections by human polyoma- and papillomaviruses. Bioorg Med Chem 22:4836-47
Neu, Ursula; Allen, Stacy-Ann A; Blaum, Barbel S et al. (2013) A structure-guided mutation in the major capsid protein retargets BK polyomavirus. PLoS Pathog 9:e1003688
Nelson, Christian D S; Carney, Dan W; Derdowski, Aaron et al. (2013) A retrograde trafficking inhibitor of ricin and Shiga-like toxins inhibits infection of cells by human and monkey polyomaviruses. MBio 4:e00729-13
Gee, Gretchen V; O'Hara, Bethany A; Derdowski, Aaron et al. (2013) Pseudovirus mimics cell entry and trafficking of the human polyomavirus JCPyV. Virus Res 178:281-6
Maginnis, Melissa S; Stroh, Luisa J; Gee, Gretchen V et al. (2013) Progressive multifocal leukoencephalopathy-associated mutations in the JC polyomavirus capsid disrupt lactoseries tetrasaccharide c binding. MBio 4:e00247-13
Lipovsky, Alex; Popa, Andreea; Pimienta, Genaro et al. (2013) Genome-wide siRNA screen identifies the retromer as a cellular entry factor for human papillomavirus. Proc Natl Acad Sci U S A 110:7452-7
Yatawara, Achani K; Hodoscek, Milan; Mierke, Dale F (2013) Ligand binding site identification by higher dimension molecular dynamics. J Chem Inf Model 53:674-80

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