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Identification of Host-Targeting Ant...

Gupta, Amita.

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Identification of Host-Targeting Antiviral Drug Combinations and Targets.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Identification of Host-Targeting Antiviral Drug Combinations and Targets./
Author:	Gupta, Amita.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
Description:	127 p.
Notes:	Source: Dissertations Abstracts International, Volume: 82-01, Section: B.
Contained By:	Dissertations Abstracts International82-01B.
Subject:	Infections. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28103838
ISBN:	9798662478503

Identification of Host-Targeting Antiviral Drug Combinations and Targets.
Gupta, Amita.

Identification of Host-Targeting Antiviral Drug Combinations and Targets. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 127 p.

Source: Dissertations Abstracts International, Volume: 82-01, Section: B.

Thesis (Ph.D.)--Stanford University, 2020.

This item must not be sold to any third party vendors.

Despite remarkable progress in the last fifty years in the fight against infectious disease, diverse viruses continue to pose major global health challenges. There is a critical need for rapidly deployable, broad-spectrum antiviral therapies. Generally, antiviral therapies are either direct-acting antivirals (DAAs) or host-targeted therapies. This thesis focuses on exploring the potential of and mechanisms underlying two distinct host-targeting antiviral strategies. Firstly, we explore combination therapies comprising inhibitors of de novo pyrimidine biosynthesis-a host-targeting antiviral strategy that has been shown to be effective in vitro against > 30 diverse DNA and RNA viruses. To improve their efficacy under physiologically relevant conditions, we combine inhibitors of the de novo pyrimidine biosynthesis with inhibitors of nucleoside salvage and transport. Using the salvage inhibitor cyclopentenyl uracil (CPU), we successfully demonstrate antiviral activity of this combination in the context of dengue infection. Furthermore, we demonstrate that the efficacy of direct-acting antivirals such as RNA-dependent RNA-polymerase (RdRp) inhibitors can be enhanced via modulation of pyrimidine biosynthesis. This proof-of-concept paves the way for dual virus and host-targeting strategies. Additionally, we perform a genome-wide analysis of human targets of the macrolide antibiotic josamycin. Macrolide antibiotics are commonly prescribed for their ability to inhibit bacterial protein synthesis. However, it is increasingly recognized that they also possess non-canonical anti-viral and other therapeutic activities in mammalian cells. To better understand their modes of action in mammalian cells, we performed a genome-wide shRNA screen in K562 cancer cells to identify genes that modulate sensitivity to josamycin. We report diverse mammalian targets including mitochondrial translation, glycolysis and the mitogen activated protein kinase (MAPK) cascade. This work demonstrates the utility of genome-wide approaches for drug target identification and uncovers human targets of this antibiotic class in an unbiased fashion.

ISBN: 9798662478503Subjects--Topical Terms:

1621997
Infections.
Subjects--Index Terms:

Pyrimidine

Identification of Host-Targeting Antiviral Drug Combinations and Targets.
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500 $a Includes supplementary digital materials.
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502 $a Thesis (Ph.D.)--Stanford University, 2020.
506 $a This item must not be sold to any third party vendors.
520 $a Despite remarkable progress in the last fifty years in the fight against infectious disease, diverse viruses continue to pose major global health challenges. There is a critical need for rapidly deployable, broad-spectrum antiviral therapies. Generally, antiviral therapies are either direct-acting antivirals (DAAs) or host-targeted therapies. This thesis focuses on exploring the potential of and mechanisms underlying two distinct host-targeting antiviral strategies. Firstly, we explore combination therapies comprising inhibitors of de novo pyrimidine biosynthesis-a host-targeting antiviral strategy that has been shown to be effective in vitro against > 30 diverse DNA and RNA viruses. To improve their efficacy under physiologically relevant conditions, we combine inhibitors of the de novo pyrimidine biosynthesis with inhibitors of nucleoside salvage and transport. Using the salvage inhibitor cyclopentenyl uracil (CPU), we successfully demonstrate antiviral activity of this combination in the context of dengue infection. Furthermore, we demonstrate that the efficacy of direct-acting antivirals such as RNA-dependent RNA-polymerase (RdRp) inhibitors can be enhanced via modulation of pyrimidine biosynthesis. This proof-of-concept paves the way for dual virus and host-targeting strategies. Additionally, we perform a genome-wide analysis of human targets of the macrolide antibiotic josamycin. Macrolide antibiotics are commonly prescribed for their ability to inhibit bacterial protein synthesis. However, it is increasingly recognized that they also possess non-canonical anti-viral and other therapeutic activities in mammalian cells. To better understand their modes of action in mammalian cells, we performed a genome-wide shRNA screen in K562 cancer cells to identify genes that modulate sensitivity to josamycin. We report diverse mammalian targets including mitochondrial translation, glycolysis and the mitogen activated protein kinase (MAPK) cascade. This work demonstrates the utility of genome-wide approaches for drug target identification and uncovers human targets of this antibiotic class in an unbiased fashion.
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650 4 $a Biosynthesis. $3 516407
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650 4 $a Kinases. $3 3558077
650 4 $a Chronic obstructive pulmonary disease. $3 3558078
650 4 $a Cell cycle. $3 766119
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650 4 $a Bioinformatics. $3 553671
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