{"id":{"repo_id":"toronto-retro","oai_identifier":"oai:utoronto.scholaris.ca:1807/139071"},"canonical_url":"https://search.dev.ndltd.org/etd/toronto-retro/oai:utoronto.scholaris.ca:1807/139071","repository":{"repo_id":"toronto-retro","name":"University of Toronto","base_url":"https://utoronto.scholaris.ca/server/oai/request"},"display":{"title":"Development of Novel Small-Molecule Therapeutics for Multiple Sclerosis","abstract":"Protein arginine deiminase (PAD) activity is upregulated in MS and the overactive enzymes convert peptidyl arginine on myelin structural proteins to neutral citrulline variants. Hypercitrullination disrupts key ionic interactions between myelin proteins and lipid bilayers that are necessary to maintain compaction within the multi-layered myelin sheath. Thus, myelin hypercitrullination reduces myelin compaction, accelerating its degradation, and the antigenic myelin debris is thought to be capable of both initiating and sustaining autoimmunity in MS. This thesis examines the utility of small molecules capable of downregulating the activity of PAD enzymes. We hypothesize PAD inhibition could serve novel ‘myelin-protective’ applications and elicit therapeutic effects independent of more traditional immunosuppression. Pharmacological downregulation of PAD activity may thus present as a first-in-class strategy targeting an underlying neurodegenerative mechanism present within MS pathophysiology. In chapter 1 of this thesis, myelin hypercitrullination and PAD inhibition are first conceptualized within the context of MS. Chapter 2, provides a background on relevant pathological mechanisms of MS, with an emphasis on the progressive stages of the disease, and reviews PAD enzymes in the context of human health and disease. Chapter 3 describes a practical synthetic procedure capable of generating multi-gram quantities of designer PAD inhibitors. Chapter 4 investigates therapeutic outcomes and explores biological mechanisms of action of our lead PAD inhibitor (KP-302) in both immunomodulatory and neurodegenerative animal models of MS. Chapter 5 explores the utility of D-amino acid analogs as PAD inhibitors with the specific aim of improving the pharmacokinetics and metabolic stability of these molecules. Chapter 6 concludes the thesis by discussing knowledge gained throughout and provides a perspective on future research directions. In the end, this thesis provides ‘drug-like’ molecular tools and assesses the medical significance of PAD inhibition as a complementary approach to immunomodulation in the management of inflammatory demyelination.","abstract_html":"Protein arginine deiminase (PAD) activity is upregulated in MS and the overactive enzymes convert peptidyl arginine on myelin structural proteins to neutral citrulline variants. Hypercitrullination disrupts key ionic interactions between myelin proteins and lipid bilayers that are necessary to maintain compaction within the multi-layered myelin sheath. Thus, myelin hypercitrullination reduces myelin compaction, accelerating its degradation, and the antigenic myelin debris is thought to be capable of both initiating and sustaining autoimmunity in MS. This thesis examines the utility of small molecules capable of downregulating the activity of PAD enzymes. We hypothesize PAD inhibition could serve novel ‘myelin-protective’ applications and elicit therapeutic effects independent of more traditional immunosuppression. Pharmacological downregulation of PAD activity may thus present as a first-in-class strategy targeting an underlying neurodegenerative mechanism present within MS pathophysiology. In chapter 1 of this thesis, myelin hypercitrullination and PAD inhibition are first conceptualized within the context of MS. Chapter 2, provides a background on relevant pathological mechanisms of MS, with an emphasis on the progressive stages of the disease, and reviews PAD enzymes in the context of human health and disease. Chapter 3 describes a practical synthetic procedure capable of generating multi-gram quantities of designer PAD inhibitors. Chapter 4 investigates therapeutic outcomes and explores biological mechanisms of action of our lead PAD inhibitor (KP-302) in both immunomodulatory and neurodegenerative animal models of MS. Chapter 5 explores the utility of D-amino acid analogs as PAD inhibitors with the specific aim of improving the pharmacokinetics and metabolic stability of these molecules. Chapter 6 concludes the thesis by discussing knowledge gained throughout and provides a perspective on future research directions. In the end, this thesis provides ‘drug-like’ molecular tools and assesses the medical significance of PAD inhibition as a complementary approach to immunomodulation in the management of inflammatory demyelination.","abstract_has_math":false,"creators":["Koebel, Adam"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":"Pharmaceutical Sciences","school":null,"contributors":[],"advisors":["Kotra, Lakshmi P"],"committee_chairs":[],"committee_members":[],"year":2022,"date_issued":"2022-06","date_published":"2022-06","updated_at":"2026-07-27T21:28:01Z","subjects":["drug discovery","multiple sclerosis","neurodegeneration","neuroprotection","PADs","protein arginine deiminase"],"languages":[],"rights":["Attribution-NonCommercial-NoDerivatives 4.0 International"],"rights_urls":["http://creativecommons.org/licenses/by-nc-nd/4.0/"],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/1807/139071","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Kotra, Lakshmi P"]},{"key":"dc:contributor.department","label":"Department","values":["Pharmaceutical Sciences"]},{"key":"dc:creator","label":"Author","values":["Koebel, Adam"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2022-06"]},{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2024-06-28T04:13:04Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2024-06-28T04:13:04Z"]},{"key":"dc:date.issued","label":"Date","values":["2022-06"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["drug discovery","multiple sclerosis","neurodegeneration","neuroprotection","PADs","protein arginine deiminase"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["Attribution-NonCommercial-NoDerivatives 4.0 International"]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://creativecommons.org/licenses/by-nc-nd/4.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/1807/139071"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Protein arginine deiminase (PAD) activity is upregulated in MS and the overactive enzymes convert peptidyl arginine on myelin structural proteins to neutral citrulline variants. Hypercitrullination disrupts key ionic interactions between myelin proteins and lipid bilayers that are necessary to maintain compaction within the multi-layered myelin sheath. Thus, myelin hypercitrullination reduces myelin compaction, accelerating its degradation, and the antigenic myelin debris is thought to be capable of both initiating and sustaining autoimmunity in MS. This thesis examines the utility of small molecules capable of downregulating the activity of PAD enzymes. We hypothesize PAD inhibition could serve novel ‘myelin-protective’ applications and elicit therapeutic effects independent of more traditional immunosuppression. Pharmacological downregulation of PAD activity may thus present as a first-in-class strategy targeting an underlying neurodegenerative mechanism present within MS pathophysiology. In chapter 1 of this thesis, myelin hypercitrullination and PAD inhibition are first conceptualized within the context of MS. Chapter 2, provides a background on relevant pathological mechanisms of MS, with an emphasis on the progressive stages of the disease, and reviews PAD enzymes in the context of human health and disease. Chapter 3 describes a practical synthetic procedure capable of generating multi-gram quantities of designer PAD inhibitors. Chapter 4 investigates therapeutic outcomes and explores biological mechanisms of action of our lead PAD inhibitor (KP-302) in both immunomodulatory and neurodegenerative animal models of MS. Chapter 5 explores the utility of D-amino acid analogs as PAD inhibitors with the specific aim of improving the pharmacokinetics and metabolic stability of these molecules. Chapter 6 concludes the thesis by discussing knowledge gained throughout and provides a perspective on future research directions. In the end, this thesis provides ‘drug-like’ molecular tools and assesses the medical significance of PAD inhibition as a complementary approach to immunomodulation in the management of inflammatory demyelination."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Ph.D."]},{"key":"dc:title","label":"Title","values":["Development of Novel Small-Molecule Therapeutics for Multiple Sclerosis"]}]}],"canonical_facts":{"dc:contributor.advisor":["Kotra, Lakshmi P"],"dc:contributor.department":["Pharmaceutical Sciences"],"dc:creator":["Koebel, Adam"],"dc:date":["2022-06"],"dc:date.accessioned":["2024-06-28T04:13:04Z"],"dc:date.available":["2024-06-28T04:13:04Z"],"dc:date.issued":["2022-06"],"dc:description.abstract":["Protein arginine deiminase (PAD) activity is upregulated in MS and the overactive enzymes convert peptidyl arginine on myelin structural proteins to neutral citrulline variants. Hypercitrullination disrupts key ionic interactions between myelin proteins and lipid bilayers that are necessary to maintain compaction within the multi-layered myelin sheath. Thus, myelin hypercitrullination reduces myelin compaction, accelerating its degradation, and the antigenic myelin debris is thought to be capable of both initiating and sustaining autoimmunity in MS. This thesis examines the utility of small molecules capable of downregulating the activity of PAD enzymes. We hypothesize PAD inhibition could serve novel ‘myelin-protective’ applications and elicit therapeutic effects independent of more traditional immunosuppression. Pharmacological downregulation of PAD activity may thus present as a first-in-class strategy targeting an underlying neurodegenerative mechanism present within MS pathophysiology. In chapter 1 of this thesis, myelin hypercitrullination and PAD inhibition are first conceptualized within the context of MS. Chapter 2, provides a background on relevant pathological mechanisms of MS, with an emphasis on the progressive stages of the disease, and reviews PAD enzymes in the context of human health and disease. Chapter 3 describes a practical synthetic procedure capable of generating multi-gram quantities of designer PAD inhibitors. Chapter 4 investigates therapeutic outcomes and explores biological mechanisms of action of our lead PAD inhibitor (KP-302) in both immunomodulatory and neurodegenerative animal models of MS. Chapter 5 explores the utility of D-amino acid analogs as PAD inhibitors with the specific aim of improving the pharmacokinetics and metabolic stability of these molecules. Chapter 6 concludes the thesis by discussing knowledge gained throughout and provides a perspective on future research directions. In the end, this thesis provides ‘drug-like’ molecular tools and assesses the medical significance of PAD inhibition as a complementary approach to immunomodulation in the management of inflammatory demyelination."],"dc:description.degree":["Ph.D."],"dc:identifier.uri":["http://hdl.handle.net/1807/139071"],"dc:rights":["Attribution-NonCommercial-NoDerivatives 4.0 International"],"dc:rights.uri":["http://creativecommons.org/licenses/by-nc-nd/4.0/"],"dc:subject":["drug discovery","multiple sclerosis","neurodegeneration","neuroprotection","PADs","protein arginine deiminase"],"dc:title":["Development of Novel Small-Molecule Therapeutics for Multiple Sclerosis"],"dc:type":["Thesis"]},"updated_at":"2026-07-27T21:28:01Z"}