This program project brings together an interdisciplinary team of three scientists with unique expertise to functionally target and inhibit human polyomavirus infections. The polyomaviruses in general, and the human polyomaviruses in particular, have been shown to utilize distinct host cell carbohydrates and proteins to infect target cells and tissues. The human polyomavirus JCV is the causative agent of a fatal central nervous system demyelinating disease known as progressive multifocal leukoencephalopathy (PML). The majority of PML cases occur in patients with AIDS but recently PML has also been shown to occur in multiple sclerosis patients being treated with potent immunomodulatory drugs that inhibit immunosurveillance of the CNS. There are currently no drugs in the pipeline that target the virus directly and a major goal of this program is to identify compounds capable of directly inhibiting virus infection. This goal will be accomplished by close collaborative interactions between a team consisting of a polyomavirologist, a structural biologist, and a structural chemist. Project # 1 led by Professor Thilo Stehle will focus on structurally characterizing and identifying sites on the virus that are critical for interacting with host cell surfaces. Project # 2 led by Professor Walter Atwood will introduce site-specific mutations in the virus based on these structures and functionally characterize the mutants for defects in assembly, DNA packaging, cell binding, cell penetration, and infection. Project # 3 led by Professor Dale Mierke will design and synthesize chemical compounds to antagonize virus host cell interactions. These compounds will be functionally screened by Project # 2. The projects will be supported by a chemical synthesis core at Dartmouth College headed by Drs. Mierke and Spaller. An administrative core will be housed at Brown University. The overall goal of this program is to use structural information to derive exquisitely specific inhibitors of polyomavirus infection that are potent, nontoxic, and bioavailable. The three major investigators on the team have built a strong working collaboration that is evidenced by the solid preliminary data supporting this application.
The research proposed in this application focuses on understanding the molecular structures involved in virus recognition of host cells. Compounds that antagonize these interactions will be developed with the long term goal of developing therapies for the treatment or prevention of the fatal central nervous system demyelinating disease Progressive Multifocal Leukoencephalopathy.
|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|
Showing the most recent 10 out of 13 publications