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Venezuelan Equine Encephalitis Virus Capsid and Host Nucleocytoplasmic Trafficking
Başlık:
Venezuelan Equine Encephalitis Virus Capsid and Host Nucleocytoplasmic Trafficking
Yazar:
Lundberg, Lindsay N., author.
ISBN:
9780438109643
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Fiziksel Tanımlama:
1 electronic resource (147 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.
Advisors: Kylene Kehn-Hall Committee members: Aarthi Narayanan; Mikell Paige; Yuntao Wu.
Özet:
Venezuelan equine encephalitis virus (VEEV) is endemic to South, Central, and North America and causes an acute, febrile-like illness in humans that occasionally progresses to neurological involvement and rarely death. It was weaponized by both the US and USSR and is a select agent and considered a Category B Pathogen by NIAID. There are no FDA-approved therapeutics or vaccines for human use. Thus, it is imperative to understand the interactions between host and viral proteins to develop targeted therapeutics that modulate host responses. VEEV capsid is known to directly interact with the host export protein, CRM1, and the import proteins, importin alpha/beta1, forming a tetrameric complex that halts nucleocytoplasmic trafficking, downregulates host transcription, and alters the cell cycle. It is hypothesized that interfering with this interaction will reduce viral titers and pathogenesis and restore dysregulated cell functions by segregating capsid during viral assembly, freeing the nuclear pore to transport cellular factors that will help counter infection and promote cell survival. To that end, in silico and in vitro compound screens were performed to identify novel inhibitors of importin alpha and capsid, yielding new scaffolds for further research. The importin alpha inhibitor mifepristone was chemically modified, generating additional compounds to test for antiviral efficacy. Novel inhibitors of export, specifically CRM1, were also tested for antiviral efficacy. Finally, the infection induced delay in G1 of the cell cycle was traced to VEEV capsid, with gene expression of cell cycle regulatory factors including multiple cyclins being altered in a capsid dependent fashion. This body of work demonstrates multiple novel chemical scaffolds targeting host proteins that interact with VEEV capsid which have the potential for further antiviral drug development.
Notlar:
School code: 0883
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(690186.1) | 690186-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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