東華大學圖書館 |

語系: 繁體中文

說明(常見問題)

回圖書館首頁

手機版館藏查詢

登入

回首頁

切換: 標籤 | MARC模式 | ISBD

FindBook

Google Book

Amazon

博客來

Host Determinants of Viral Entry and Replication.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Host Determinants of Viral Entry and Replication./
作者:	Tartell, Michael Armen.
面頁冊數:	1 online resource (302 pages)
附註:	Source: Dissertations Abstracts International, Volume: 83-12, Section: B.
Contained By:	Dissertations Abstracts International83-12B.
標題:	Virology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=29209054click for full text (PQDT)
ISBN:	9798819382011

Host Determinants of Viral Entry and Replication.
Tartell, Michael Armen.

Host Determinants of Viral Entry and Replication. - 1 online resource (302 pages)

Source: Dissertations Abstracts International, Volume: 83-12, Section: B.

Thesis (Ph.D.)--Harvard University, 2022.

Includes bibliographical references

As obligate intracellular parasites, viruses rely on the biological machinery of their hosts to replicate. Each step of the viral life cycle, from entry, to protein translation and genome replication, to egress, involves host factors and their associated mechanisms to function. The presence of these factors, and the virus's ability to exploit them by mimicking the host, can determine the success of viral infection. Cells in turn have evolved mechanisms to defeat viral subversion, including self/non-self recognition by the innate immune system, and cell-intrinsic responses induced by interferons. Using vesicular stomatitis virus (VSV), we found that the host N6-adenosine messenger RNA (mRNA) cap methyltransferase, phosphorylated C-terminal domain interacting factor 1 (PCIF1), attenuates the antiviral response to interferon-beta (IFN-β). PCIF1 N6-methylates the cap-proximal nucleotide of VSV mRNA to m7Gpppm6Am, and we define substrate requirements for this modification. PCIF1-dependent N6-methylation had no impact on mRNA stability, translation, or viral infectivity. However, cells lacking PCIF1 or expressing a catalytically inactive PCIF1 exhibit an augmented inhibition of viral replication and gene expression following IFN-β pretreatment. We further demonstrate that mRNA cap structures of rabies and measles viruses are also modified by PCIF1. This identifies a function of PCIF1 and cap-proximal m6Am in attenuation of the host response to viral infection. Host factors, specifically host proteases, are required to trigger membrane fusion and entry of coronaviruses into cells, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The serine protease TMPRSS2 fulfills this function in lung cells, and is an attractive therapeutic target for antiviral drugs against COVID-19. Using rational structure-based drug design, substrate specificity screening of TMPRSS2, and entry inhibition screening using infectious chimeric VSV-SARS-CoV-2, we discovered covalent small-molecule ketobenzothiazole (kbt) TMPRSS2 inhibitors which are structurally distinct from and have improved activity over existing inhibitors Camostat and Nafamostat. Lead compound MM3122 has a half-maximal inhibitory concentration (IC50) of 430 pM in blocking entry of VSV-SARS-CoV-2 into Calu-3 human lung epithelial cells, and a similar IC50 of 870 pM against a chimeric VSV Middle East respiratory syndrome coronavirus (VSV-MERS-CoV). Excellent metabolic stability, safety, and pharmacokinetics in mice make it a promising drug candidate for COVID-19 treatment.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798819382011Subjects--Topical Terms:

642304
Virology.
Subjects--Index Terms:

COVID-19Index Terms--Genre/Form:

542853
Electronic books.

Host Determinants of Viral Entry and Replication.
LDR:04012nmm a2200433K 4500 001 2359783
005 20230917195245.5
006 m o d
007 cr mn ---uuuuu
008 241011s2022 xx obm 000 0 eng d
020 $a 9798819382011
035 $a (MiAaPQ)AAI29209054
035 $a AAI29209054
040 $a MiAaPQ $b eng $c MiAaPQ $d NTU
100 1 $a Tartell, Michael Armen. $3 3700399
245 1 0 $a Host Determinants of Viral Entry and Replication.
264 0 $c 2022
300 $a 1 online resource (302 pages)
336 $a text $b txt $2 rdacontent
337 $a computer $b c $2 rdamedia
338 $a online resource $b cr $2 rdacarrier
500 $a Source: Dissertations Abstracts International, Volume: 83-12, Section: B.
500 $a Advisor: Whelan, Sean P. J.
502 $a Thesis (Ph.D.)--Harvard University, 2022.
504 $a Includes bibliographical references
520 $a As obligate intracellular parasites, viruses rely on the biological machinery of their hosts to replicate. Each step of the viral life cycle, from entry, to protein translation and genome replication, to egress, involves host factors and their associated mechanisms to function. The presence of these factors, and the virus's ability to exploit them by mimicking the host, can determine the success of viral infection. Cells in turn have evolved mechanisms to defeat viral subversion, including self/non-self recognition by the innate immune system, and cell-intrinsic responses induced by interferons. Using vesicular stomatitis virus (VSV), we found that the host N6-adenosine messenger RNA (mRNA) cap methyltransferase, phosphorylated C-terminal domain interacting factor 1 (PCIF1), attenuates the antiviral response to interferon-beta (IFN-β). PCIF1 N6-methylates the cap-proximal nucleotide of VSV mRNA to m7Gpppm6Am, and we define substrate requirements for this modification. PCIF1-dependent N6-methylation had no impact on mRNA stability, translation, or viral infectivity. However, cells lacking PCIF1 or expressing a catalytically inactive PCIF1 exhibit an augmented inhibition of viral replication and gene expression following IFN-β pretreatment. We further demonstrate that mRNA cap structures of rabies and measles viruses are also modified by PCIF1. This identifies a function of PCIF1 and cap-proximal m6Am in attenuation of the host response to viral infection. Host factors, specifically host proteases, are required to trigger membrane fusion and entry of coronaviruses into cells, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The serine protease TMPRSS2 fulfills this function in lung cells, and is an attractive therapeutic target for antiviral drugs against COVID-19. Using rational structure-based drug design, substrate specificity screening of TMPRSS2, and entry inhibition screening using infectious chimeric VSV-SARS-CoV-2, we discovered covalent small-molecule ketobenzothiazole (kbt) TMPRSS2 inhibitors which are structurally distinct from and have improved activity over existing inhibitors Camostat and Nafamostat. Lead compound MM3122 has a half-maximal inhibitory concentration (IC50) of 430 pM in blocking entry of VSV-SARS-CoV-2 into Calu-3 human lung epithelial cells, and a similar IC50 of 870 pM against a chimeric VSV Middle East respiratory syndrome coronavirus (VSV-MERS-CoV). Excellent metabolic stability, safety, and pharmacokinetics in mice make it a promising drug candidate for COVID-19 treatment.
533 $a Electronic reproduction. $b Ann Arbor, Mich. : $c ProQuest, $d 2023
538 $a Mode of access: World Wide Web
650 4 $a Virology. $3 642304
650 4 $a Cellular biology. $3 3172791
650 4 $a Pharmacology. $3 634543
650 4 $a Molecular biology. $3 517296
650 4 $a Immunology. $3 611031
650 4 $a COVID-19. $3 3554449
653 $a COVID-19
653 $a Host-pathogen interactions
653 $a Innate immunity
653 $a Protease inhibitor
653 $a RNA modifications
653 $a Structure-based drug discovery
655 7 $a Electronic books. $2 lcsh $3 542853
690 $a 0720
690 $a 0379
690 $a 0982
690 $a 0419
690 $a 0307
710 2 $a ProQuest Information and Learning Co. $3 783688
710 2 $a Harvard University. $b Medical Sciences. $3 3181716
773 0 $t Dissertations Abstracts International $g 83-12B.
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=29209054 $z click for full text (PQDT)