{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/369956"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/369956","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Evolution of targets at the host-pathogen interface","abstract":"Chapter 1: Introduction <br>Background information of the origin, pathophysiology, and therapeutic options for both the bacterial pathogen Mycobacterium tuberculosis (Mtb) and betacoronaviruses – the Severe Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) in particular – is presented. Chapter 2: Protein-coding potential of the Mtb genome <br>Using comparative genomics, I investigate the protein-coding potential of globally-distributed Mtb strains. Previous reports had suggested that the pan-genome (or all unique protein coding sequences among all strains) gets larger with each analyzed genome. After correcting for bioinformatics artefacts, the constructed Mtb pan-genome suggests that the proteome is stable (or potentially decreasing in size). These findings reveal that there are a high number of conserved drug targets that can be selected as candidates for drug discovery campaigns and shed light on Mtb biology and pathogenesis. Chapter 3: Drug targets in the Mtb proteome <br>Cross-examination of the resultant Mtb pan-genome genes with existing essentiality and druggability data, however, indicate that only a few proteins – 9 in this study – may be agreed upon as high confidence drug targets. Two protein targets were preliminarily assessed for their druggability: Mtb RecA protein (which contributes to persistence in the presence of first-line antibiotics) and cofactor F420-binding proteins (which bind to a microorganism-specific cofactor, regulate various processes, and can be targeted with one drug) primarily using in silico biochemical methodologies. Chapter 4: SARS-CoV-2 proteome modelling and drug target assessment <br>In this chapter, I explore the 3D protein structure modelling and functional annotation of overlapping ORFs on the positive- and negative-sense strands of the SARS-CoV-2 genome. The structural implications of post-translational modifications, such as glycosylation, are also examined. In summary, the small proteins are predicted to interact in a wide variety of intracellular signaling pathways. These results provide the basis for further analyses into the structure-function relationship and druggability of SARS-CoV-2 proteins. Chapter 5: Evolution of SARS-CoV-2 cell entry <br>The evolution of molecular mimicry mechanisms by the SARS-CoV-2, SARS-CoV-1, and MERS-CoV spike-receptor are explored. In short, diverse protein classes were predicted to interact with the spike protein, which suggest novel host cell receptors. The potential for the SARS-CoV-2 spike protein to bind to integrins – independent of the canonical RGD motif – as a cell entry receptor was investigated. Bioinformatics studies to determine the potential effect of post-translational modifications on spike protein cleavage – a necessary step for membrane fusion – in the spike proteins of variants of concern were also conducted. Chapter 6: Conclusions and Future Directions <br>The Mtb pan-genome and its druggability are discussed based on the findings in this study. The evolution of the SARS-CoV-2 proteome is elaborated upon in the context of the thesis data.","abstract_html":"Chapter 1: Introduction &lt;br&gt;Background information of the origin, pathophysiology, and therapeutic options for both the bacterial pathogen Mycobacterium tuberculosis (Mtb) and betacoronaviruses – the Severe Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) in particular – is presented. Chapter 2: Protein-coding potential of the Mtb genome &lt;br&gt;Using comparative genomics, I investigate the protein-coding potential of globally-distributed Mtb strains. Previous reports had suggested that the pan-genome (or all unique protein coding sequences among all strains) gets larger with each analyzed genome. After correcting for bioinformatics artefacts, the constructed Mtb pan-genome suggests that the proteome is stable (or potentially decreasing in size). These findings reveal that there are a high number of conserved drug targets that can be selected as candidates for drug discovery campaigns and shed light on Mtb biology and pathogenesis. Chapter 3: Drug targets in the Mtb proteome &lt;br&gt;Cross-examination of the resultant Mtb pan-genome genes with existing essentiality and druggability data, however, indicate that only a few proteins – 9 in this study – may be agreed upon as high confidence drug targets. Two protein targets were preliminarily assessed for their druggability: Mtb RecA protein (which contributes to persistence in the presence of first-line antibiotics) and cofactor F420-binding proteins (which bind to a microorganism-specific cofactor, regulate various processes, and can be targeted with one drug) primarily using in silico biochemical methodologies. Chapter 4: SARS-CoV-2 proteome modelling and drug target assessment &lt;br&gt;In this chapter, I explore the 3D protein structure modelling and functional annotation of overlapping ORFs on the positive- and negative-sense strands of the SARS-CoV-2 genome. The structural implications of post-translational modifications, such as glycosylation, are also examined. In summary, the small proteins are predicted to interact in a wide variety of intracellular signaling pathways. These results provide the basis for further analyses into the structure-function relationship and druggability of SARS-CoV-2 proteins. Chapter 5: Evolution of SARS-CoV-2 cell entry &lt;br&gt;The evolution of molecular mimicry mechanisms by the SARS-CoV-2, SARS-CoV-1, and MERS-CoV spike-receptor are explored. In short, diverse protein classes were predicted to interact with the spike protein, which suggest novel host cell receptors. The potential for the SARS-CoV-2 spike protein to bind to integrins – independent of the canonical RGD motif – as a cell entry receptor was investigated. Bioinformatics studies to determine the potential effect of post-translational modifications on spike protein cleavage – a necessary step for membrane fusion – in the spike proteins of variants of concern were also conducted. Chapter 6: Conclusions and Future Directions &lt;br&gt;The Mtb pan-genome and its druggability are discussed based on the findings in this study. The evolution of the SARS-CoV-2 proteome is elaborated upon in the context of the thesis data.","abstract_has_math":false,"creators":["Beaudoin, Christopher"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Blundell, Thomas","Jackson, Antony"],"committee_chairs":[],"committee_members":[],"year":2023,"date_issued":"2023-07-06","date_published":"2023-07-06","updated_at":"2026-07-22T22:23:53Z","subjects":["Biochemistry","Drug target","Host-pathogen interface","Mycobacterium tuberculosis","pan-genome","SARS-CoV-2","spike protein"],"languages":["eng"],"rights":[],"rights_urls":["https://www.repository.cam.ac.uk/bitstreams/c9649e72-a880-4923-ace1-81b8bd66c349/download","https://creativecommons.org/licenses/by-nd/4.0/"],"identifier_entries":[{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000202320281"],"render_values":[{"text":"0000-0002-0232-0281","href":"https://orcid.org/0000-0002-0232-0281","code":true}]}]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.109545","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Blundell, Thomas","Jackson, Antony"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["Antibiotic Research UK (ANTSRG 01/2019-PHZJ/687)"]},{"key":"dc:creator","label":"Author","values":["Beaudoin, Christopher"]},{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000202320281"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2023-07-06"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/369956"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Biochemistry","Drug target","Host-pathogen interface","Mycobacterium tuberculosis","pan-genome","SARS-CoV-2","spike protein"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://www.repository.cam.ac.uk/bitstreams/c9649e72-a880-4923-ace1-81b8bd66c349/download","https://creativecommons.org/licenses/by-nd/4.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.17863/CAM.109545"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://www.repository.cam.ac.uk/bitstreams/574aad93-429f-4cbd-a7da-516753f93a33/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Chapter 1: Introduction <br>Background information of the origin, pathophysiology, and therapeutic options for both the bacterial pathogen Mycobacterium tuberculosis (Mtb) and betacoronaviruses – the Severe Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) in particular – is presented. Chapter 2: Protein-coding potential of the Mtb genome <br>Using comparative genomics, I investigate the protein-coding potential of globally-distributed Mtb strains. Previous reports had suggested that the pan-genome (or all unique protein coding sequences among all strains) gets larger with each analyzed genome. After correcting for bioinformatics artefacts, the constructed Mtb pan-genome suggests that the proteome is stable (or potentially decreasing in size). These findings reveal that there are a high number of conserved drug targets that can be selected as candidates for drug discovery campaigns and shed light on Mtb biology and pathogenesis. Chapter 3: Drug targets in the Mtb proteome <br>Cross-examination of the resultant Mtb pan-genome genes with existing essentiality and druggability data, however, indicate that only a few proteins – 9 in this study – may be agreed upon as high confidence drug targets. Two protein targets were preliminarily assessed for their druggability: Mtb RecA protein (which contributes to persistence in the presence of first-line antibiotics) and cofactor F420-binding proteins (which bind to a microorganism-specific cofactor, regulate various processes, and can be targeted with one drug) primarily using in silico biochemical methodologies. Chapter 4: SARS-CoV-2 proteome modelling and drug target assessment <br>In this chapter, I explore the 3D protein structure modelling and functional annotation of overlapping ORFs on the positive- and negative-sense strands of the SARS-CoV-2 genome. The structural implications of post-translational modifications, such as glycosylation, are also examined. In summary, the small proteins are predicted to interact in a wide variety of intracellular signaling pathways. These results provide the basis for further analyses into the structure-function relationship and druggability of SARS-CoV-2 proteins. Chapter 5: Evolution of SARS-CoV-2 cell entry <br>The evolution of molecular mimicry mechanisms by the SARS-CoV-2, SARS-CoV-1, and MERS-CoV spike-receptor are explored. In short, diverse protein classes were predicted to interact with the spike protein, which suggest novel host cell receptors. The potential for the SARS-CoV-2 spike protein to bind to integrins – independent of the canonical RGD motif – as a cell entry receptor was investigated. Bioinformatics studies to determine the potential effect of post-translational modifications on spike protein cleavage – a necessary step for membrane fusion – in the spike proteins of variants of concern were also conducted. Chapter 6: Conclusions and Future Directions <br>The Mtb pan-genome and its druggability are discussed based on the findings in this study. 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Chapter 2: Protein-coding potential of the Mtb genome <br>Using comparative genomics, I investigate the protein-coding potential of globally-distributed Mtb strains. Previous reports had suggested that the pan-genome (or all unique protein coding sequences among all strains) gets larger with each analyzed genome. After correcting for bioinformatics artefacts, the constructed Mtb pan-genome suggests that the proteome is stable (or potentially decreasing in size). These findings reveal that there are a high number of conserved drug targets that can be selected as candidates for drug discovery campaigns and shed light on Mtb biology and pathogenesis. Chapter 3: Drug targets in the Mtb proteome <br>Cross-examination of the resultant Mtb pan-genome genes with existing essentiality and druggability data, however, indicate that only a few proteins – 9 in this study – may be agreed upon as high confidence drug targets. Two protein targets were preliminarily assessed for their druggability: Mtb RecA protein (which contributes to persistence in the presence of first-line antibiotics) and cofactor F420-binding proteins (which bind to a microorganism-specific cofactor, regulate various processes, and can be targeted with one drug) primarily using in silico biochemical methodologies. Chapter 4: SARS-CoV-2 proteome modelling and drug target assessment <br>In this chapter, I explore the 3D protein structure modelling and functional annotation of overlapping ORFs on the positive- and negative-sense strands of the SARS-CoV-2 genome. The structural implications of post-translational modifications, such as glycosylation, are also examined. In summary, the small proteins are predicted to interact in a wide variety of intracellular signaling pathways. These results provide the basis for further analyses into the structure-function relationship and druggability of SARS-CoV-2 proteins. Chapter 5: Evolution of SARS-CoV-2 cell entry <br>The evolution of molecular mimicry mechanisms by the SARS-CoV-2, SARS-CoV-1, and MERS-CoV spike-receptor are explored. In short, diverse protein classes were predicted to interact with the spike protein, which suggest novel host cell receptors. The potential for the SARS-CoV-2 spike protein to bind to integrins – independent of the canonical RGD motif – as a cell entry receptor was investigated. Bioinformatics studies to determine the potential effect of post-translational modifications on spike protein cleavage – a necessary step for membrane fusion – in the spike proteins of variants of concern were also conducted. Chapter 6: Conclusions and Future Directions <br>The Mtb pan-genome and its druggability are discussed based on the findings in this study. 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