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

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Structural and Functional Approaches to Broaden Our Understanding of Coronavirus Replication Complexes // Thomas K Anderson.
作者:	Anderson, Thomas K.,
面頁冊數:	1 electronic resource (352 pages)
附註:	Source: Dissertations Abstracts International, Volume: 86-01, Section: B.
提要註:	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.
標題:	Molecular biology. -
電子資源:	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 /
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