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Exploring Dengue Virus Entry Through...

Clark, Margaret Jean.

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Exploring Dengue Virus Entry Through Small Molecule Inhibition and Mutagenesis of the Envelope Protein.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Exploring Dengue Virus Entry Through Small Molecule Inhibition and Mutagenesis of the Envelope Protein./
Author:	Clark, Margaret Jean.
Description:	166 p.
Notes:	Source: Dissertation Abstracts International, Volume: 74-06(E), Section: B.
Contained By:	Dissertation Abstracts International74-06B(E).
Subject:	Virology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3553409
ISBN:	9781267928849

Exploring Dengue Virus Entry Through Small Molecule Inhibition and Mutagenesis of the Envelope Protein.
Clark, Margaret Jean.

Exploring Dengue Virus Entry Through Small Molecule Inhibition and Mutagenesis of the Envelope Protein. - 166 p.

Source: Dissertation Abstracts International, Volume: 74-06(E), Section: B.

Thesis (Ph.D.)--Harvard University, 2014.

This item is not available from ProQuest Dissertations & Theses.

Over one-third of the world's population is at risk for infection with dengue virus (DENV), a mosquito-borne virus that can cause a severe febrile disease. There are no specific treatments available for dengue infection, and much remains unknown about how DENV interaction with the host cell leads to a successful infection. This dissertation examines DENV entry using small molecule inhibitors and mutagenesis of the envelope (E) protein, the major protein on the viral surface.

ISBN: 9781267928849Subjects--Topical Terms:

642304
Virology.

Exploring Dengue Virus Entry Through Small Molecule Inhibition and Mutagenesis of the Envelope Protein.
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020 $a 9781267928849
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100 1 $a Clark, Margaret Jean. $3 3173860
245 1 0 $a Exploring Dengue Virus Entry Through Small Molecule Inhibition and Mutagenesis of the Envelope Protein.
300 $a 166 p.
500 $a Source: Dissertation Abstracts International, Volume: 74-06(E), Section: B.
500 $a Adviser: Priscilla L. Yang.
502 $a Thesis (Ph.D.)--Harvard University, 2014.
506 $a This item is not available from ProQuest Dissertations & Theses.
506 $a This item must not be sold to any third party vendors.
520 $a Over one-third of the world's population is at risk for infection with dengue virus (DENV), a mosquito-borne virus that can cause a severe febrile disease. There are no specific treatments available for dengue infection, and much remains unknown about how DENV interaction with the host cell leads to a successful infection. This dissertation examines DENV entry using small molecule inhibitors and mutagenesis of the envelope (E) protein, the major protein on the viral surface.
520 $a This work grew from our initial observation that small molecule GNF-2 is capable of lowering DENV yield when present at two separate points during DENV infection. Treatment of infected cells with GNF-2 post-entry significantly lowered DENV yield, most likely due to GNF-2's documented activity against Abl kinase. However, we also observed that treatment of virus inocula with GNF-2 prior to cellular infection significantly lowered DENV yield. We discovered that GNF-2 bound directly to the dengue virion and co-localized with DENV envelope protein shortly after cellular infection. Using GNF-2 as a scaffold, we performed a structure-activity relationship study and identified twenty-one compounds that have similar or increased potency as GNF-2 when pre-incubated with virus. Using a subset of compounds from this study, we demonstrated that they block completion of DENV fusion in vitro, suggesting that the compounds inhibit DENV entry by preventing the completion of viral fusion inside cellular endosomes.
520 $a In experiments complementing the mechanism of action studies, we selected for inhibitor-resistant virus by passaging virus in the presence of small molecules. We identified a single point mutation in the envelope protein located in the domain I/II interface that enhanced viral entry and conferred resistance to virus particles against select compounds in a single-cycle reporter virus system. Further examination of this E protein "hinge region" found that mutations in this area may affect both release and entry of reporter virus particles. The work presented in this dissertation may inform the design of future small molecule inhibitors of DENV as well as increase our understanding of how point mutations in the DENV E protein can influence viral entry and other steps of the viral life cycle.
590 $a School code: 0084.
650 4 $a Virology. $3 642304
650 4 $a Molecular biology. $3 517296
650 4 $a Biochemistry. $3 518028
690 $a 0720
690 $a 0307
690 $a 0487
710 2 $a Harvard University. $b Biology: Medical Sciences, Division of. $3 2097738
773 0 $t Dissertation Abstracts International $g 74-06B(E).
790 $a 0084
791 $a Ph.D.
792 $a 2014
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3553409