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Evolution of targets at the host-pathogen interface https://doi.org/10.17863/CAM.109545 Beaudoin, Christopher 0000000202320281 Blundell, Thomas Jackson, Antony Chapter 1: Introduction 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 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 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 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 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 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. University of Cambridge 2023-07-06 Thesis Doctoral Doctor of Philosophy (PhD) eng Antibiotic Research UK (ANTSRG 01/2019-PHZJ/687) https://www.repository.cam.ac.uk/handle/1810/369956 https://www.repository.cam.ac.uk/bitstreams/574aad93-429f-4cbd-a7da-516753f93a33/download 17b65a3f9c6f1a27f69b77960e189c52 https://www.repository.cam.ac.uk/bitstreams/c9649e72-a880-4923-ace1-81b8bd66c349/download 87eda9de84448d1f82354d60eee3eb5f https://creativecommons.org/licenses/by-nd/4.0/ Biochemistry Drug target Host-pathogen interface Mycobacterium tuberculosis pan-genome SARS-CoV-2 spike protein