高雄醫學大學圖書館 |

Structural and Functional Approaches to Broaden Our Understanding of Coronavirus Replication Complexes /

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Structural and Functional Approaches to Broaden Our Understanding of Coronavirus Replication Complexes // Thomas K Anderson.
Author:	Anderson, Thomas K.,
Description:	1 electronic resource (352 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-01, Section: B.
基督教聖經之智慧書導讀 :	Coronaviruses (CoVs) are a subfamily of viruses with a propensity to cross over from animal reservoirs into humans, causing epidemics or pandemics. In recent history, there have been three such spillovers: SARS-CoV, MERS-CoV, and SARS-CoV-2, which is the causative agent of COVID-19. CoVs are RNA viruses with uniquely large, ~30 kb (+) single-stranded RNA genomes. Coronaviruses encode over a dozen proteins that are believed to interact and form a viral replication-transcription complex (RTC) that is responsible for the synthesis, capping, and proofreading of viral RNA during an infection. Since the onset of the COVID-19 pandemic, the SARS-CoV-2 RTC has been a focus for biochemical and structural biology studies. The RTC is also a main target for antiviral drug development, with two nucleoside analogue antivirals receiving emergency use authorization for the treatment of COVID-19. Understanding the enzymatic mechanisms by which CoVs replicate and modify their RNA is critical for our ability to develop more antivirals against CoVs to prepare us for future CoV spillovers and diseases.Most studies on CoV replication have focused on Betacoronaviruses, in particular SARS-CoV-2, leaving other genera drastically understudied. Here, we report the first three structures of non-Betacoronavirus RTCs, two from the Alphacoronavirus genera and one from the Gammacoronavirus genera. In solving these structures, we identified conserved RTC replication cofactor functions and requirements, while also demonstrating the potential for genera specific pathways of RTC assembly. This work demonstrates the importance of studying a broad range of CoVs. CoVs unique ability to proofread has been well documented but the mechanism by which it occurs remains unknown. Here I present the substrate requirements for the interaction of the CoV RTC and proofreading complex. Further, I have narrowed down the potential interaction site of these two complexes. This work provides critical insight into the unique mechanism of CoV proofreading. To aid in the development of CoV antivirals we solved the structure of a SARSCoV-2 RTC that's elongation is stalled by an arabinose nucleotide. In solving this structure, we identified that arabinose nucleotides are potent inhibitors of the CoV RTC. To our knowledge the use of arabinose nucleotides as CoV antivirals has not been previously tested. Our work demonstrates that these nucleoside analogues have the potential to be used as templates for antiviral drug development. The work presented here provides critical insight into the mechanisms of CoV replication and proofreading, aiding in our ability to design more potent and broadly acting CoV antivirals, helping treat current and future CoV induced diseases.
Contained By:	Dissertations Abstracts International86-01B.
Subject:	Molecular biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31483513
ISBN:	9798383227930

Structural and Functional Approaches to Broaden Our Understanding of Coronavirus Replication Complexes /
Anderson, Thomas K.,

Structural and Functional Approaches to Broaden Our Understanding of Coronavirus Replication Complexes /Thomas K Anderson. - 1 electronic resource (352 pages)

Source: Dissertations Abstracts International, Volume: 86-01, Section: B.

Coronaviruses (CoVs) are a subfamily of viruses with a propensity to cross over from animal reservoirs into humans, causing epidemics or pandemics. In recent history, there have been three such spillovers: SARS-CoV, MERS-CoV, and SARS-CoV-2, which is the causative agent of COVID-19. CoVs are RNA viruses with uniquely large, ~30 kb (+) single-stranded RNA genomes. Coronaviruses encode over a dozen proteins that are believed to interact and form a viral replication-transcription complex (RTC) that is responsible for the synthesis, capping, and proofreading of viral RNA during an infection. Since the onset of the COVID-19 pandemic, the SARS-CoV-2 RTC has been a focus for biochemical and structural biology studies. The RTC is also a main target for antiviral drug development, with two nucleoside analogue antivirals receiving emergency use authorization for the treatment of COVID-19. Understanding the enzymatic mechanisms by which CoVs replicate and modify their RNA is critical for our ability to develop more antivirals against CoVs to prepare us for future CoV spillovers and diseases.Most studies on CoV replication have focused on Betacoronaviruses, in particular SARS-CoV-2, leaving other genera drastically understudied. Here, we report the first three structures of non-Betacoronavirus RTCs, two from the Alphacoronavirus genera and one from the Gammacoronavirus genera. In solving these structures, we identified conserved RTC replication cofactor functions and requirements, while also demonstrating the potential for genera specific pathways of RTC assembly. This work demonstrates the importance of studying a broad range of CoVs. CoVs unique ability to proofread has been well documented but the mechanism by which it occurs remains unknown. Here I present the substrate requirements for the interaction of the CoV RTC and proofreading complex. Further, I have narrowed down the potential interaction site of these two complexes. This work provides critical insight into the unique mechanism of CoV proofreading. To aid in the development of CoV antivirals we solved the structure of a SARSCoV-2 RTC that's elongation is stalled by an arabinose nucleotide. In solving this structure, we identified that arabinose nucleotides are potent inhibitors of the CoV RTC. To our knowledge the use of arabinose nucleotides as CoV antivirals has not been previously tested. Our work demonstrates that these nucleoside analogues have the potential to be used as templates for antiviral drug development. The work presented here provides critical insight into the mechanisms of CoV replication and proofreading, aiding in our ability to design more potent and broadly acting CoV antivirals, helping treat current and future CoV induced diseases.

English

ISBN: 9798383227930Subjects--Topical Terms:

214456
Molecular biology.
Subjects--Index Terms:

Coronaviruses

Structural and Functional Approaches to Broaden Our Understanding of Coronavirus Replication Complexes /
LDR:04355nam a22004453i 4500 001 391448
005 20251124054758.5
006 m o d
007 cr|nu||||||||
008 251208s2024 miu||||||m |||||||eng d
020 $a 9798383227930
035 $a (MiAaPQD)AAI31483513
035 $a AAI31483513
040 $a MiAaPQD $b eng $c MiAaPQD $e rda
100 1 $a Anderson, Thomas K., $e author. $3 523939
245 1 0 $a Structural and Functional Approaches to Broaden Our Understanding of Coronavirus Replication Complexes / $c Thomas K Anderson.
264 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2024
300 $a 1 electronic resource (352 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: 86-01, Section: B.
500 $a Advisors: Kirchdoerfer, Robert Committee members: Bernard, Kristen; Butcher, Samuel; Sherer, Nathan; Peersen, Olve; Mehle, Andrew.
502 $b Ph.D. $c The University of Wisconsin - Madison $d 2024.
520 $a Coronaviruses (CoVs) are a subfamily of viruses with a propensity to cross over from animal reservoirs into humans, causing epidemics or pandemics. In recent history, there have been three such spillovers: SARS-CoV, MERS-CoV, and SARS-CoV-2, which is the causative agent of COVID-19. CoVs are RNA viruses with uniquely large, ~30 kb (+) single-stranded RNA genomes. Coronaviruses encode over a dozen proteins that are believed to interact and form a viral replication-transcription complex (RTC) that is responsible for the synthesis, capping, and proofreading of viral RNA during an infection. Since the onset of the COVID-19 pandemic, the SARS-CoV-2 RTC has been a focus for biochemical and structural biology studies. The RTC is also a main target for antiviral drug development, with two nucleoside analogue antivirals receiving emergency use authorization for the treatment of COVID-19. Understanding the enzymatic mechanisms by which CoVs replicate and modify their RNA is critical for our ability to develop more antivirals against CoVs to prepare us for future CoV spillovers and diseases.Most studies on CoV replication have focused on Betacoronaviruses, in particular SARS-CoV-2, leaving other genera drastically understudied. Here, we report the first three structures of non-Betacoronavirus RTCs, two from the Alphacoronavirus genera and one from the Gammacoronavirus genera. In solving these structures, we identified conserved RTC replication cofactor functions and requirements, while also demonstrating the potential for genera specific pathways of RTC assembly. This work demonstrates the importance of studying a broad range of CoVs. CoVs unique ability to proofread has been well documented but the mechanism by which it occurs remains unknown. Here I present the substrate requirements for the interaction of the CoV RTC and proofreading complex. Further, I have narrowed down the potential interaction site of these two complexes. This work provides critical insight into the unique mechanism of CoV proofreading. To aid in the development of CoV antivirals we solved the structure of a SARSCoV-2 RTC that's elongation is stalled by an arabinose nucleotide. In solving this structure, we identified that arabinose nucleotides are potent inhibitors of the CoV RTC. To our knowledge the use of arabinose nucleotides as CoV antivirals has not been previously tested. Our work demonstrates that these nucleoside analogues have the potential to be used as templates for antiviral drug development. The work presented here provides critical insight into the mechanisms of CoV replication and proofreading, aiding in our ability to design more potent and broadly acting CoV antivirals, helping treat current and future CoV induced diseases.
546 $a English
590 $a School code: 0262
650 4 $2 96060 $a Molecular biology. $3 214456
650 4 $a Cellular biology. $3 523871
650 4 $2 96060 $a Virology. $3 187922
650 4 $2 96060 $a Biochemistry. $3 186550
653 $a Coronaviruses
653 $a Polymerases
653 $a Ribonucleic acid
653 $a Betacoronaviruses
653 $a Replication-transcription complex
690 $a 0487
690 $a 0720
690 $a 0379
690 $a 0307
710 2 $a The University of Wisconsin - Madison. $b Cellular and Molecular Biology. $e degree granting institution. $3 523940
720 1 $a Kirchdoerfer, Robert $e degree supervisor.
773 0 $t Dissertations Abstracts International $g 86-01B.
790 $a 0262
791 $a Ph.D.
792 $a 2024
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31483513