{"id":{"repo_id":"purdue-thes","oai_identifier":"oai:docs.lib.purdue.edu:open_access_dissertations-2305"},"canonical_url":"https://search.dev.ndltd.org/etd/purdue-thes/oai:docs.lib.purdue.edu:open_access_dissertations-2305","repository":{"repo_id":"purdue-thes","name":"Purdue University","base_url":"https://docs.lib.purdue.edu/do/oai/"},"display":{"title":"Discovery of Molecules that Modulate Protein-Protein Interactions in the Context of Human Proliferating Cell Nuclear Antigen-Associated Processes of DNA Replication and Damage Repair","abstract":"Integral to cell viability is the homotrimeric protein complex Proliferating Cell Nuclear Antigen (PCNA) that encircles chromatin-bound DNA and functionally acts as a DNA clamp that provides topological sites for recruitment of proteins necessary for DNA replication and damage repair. PCNA has critical roles in the survival and proliferation of cells, as disease-associated dysregulation of associated functions can have dire effects on genome stability, leading to the formation of various malignancies ranging from non-Hodgkin’s lymphoma to skin, laryngeal, ocular, prostate and breast cancers. Here, a strategy was explored with PCNA as a drug target that may have wider implications for targeting protein-protein interactions (PPIs) as well as for fragment-based drug design. A design platform using peptidomimetic small molecules was developed that maps ideal surface binding interaction sites at a PPI interface before considering detailed conformations of an optimal ligand. A novel in silico multi-fragment, combinatorial screening approach was used to guide the selection and subsequent synthesis of tripeptoid ligands, which were evaluated in a PCNA-based competitive displacement assay. From the results, some of the peptoid-based compounds that were synthesized displayed the ability to disrupt the interaction between PCNA and a PIP box-containing peptide. The IC50 values of these compounds had similar or improved affinity to that of T2AA, an established inhibitor of PCNA-PIP box interactions. The information gained here could be useful for subsequent drug lead candidate identification.","abstract_html":"Integral to cell viability is the homotrimeric protein complex Proliferating Cell Nuclear Antigen (PCNA) that encircles chromatin-bound DNA and functionally acts as a DNA clamp that provides topological sites for recruitment of proteins necessary for DNA replication and damage repair. PCNA has critical roles in the survival and proliferation of cells, as disease-associated dysregulation of associated functions can have dire effects on genome stability, leading to the formation of various malignancies ranging from non-Hodgkin’s lymphoma to skin, laryngeal, ocular, prostate and breast cancers. Here, a strategy was explored with PCNA as a drug target that may have wider implications for targeting protein-protein interactions (PPIs) as well as for fragment-based drug design. A design platform using peptidomimetic small molecules was developed that maps ideal surface binding interaction sites at a PPI interface before considering detailed conformations of an optimal ligand. A novel in silico multi-fragment, combinatorial screening approach was used to guide the selection and subsequent synthesis of tripeptoid ligands, which were evaluated in a PCNA-based competitive displacement assay. From the results, some of the peptoid-based compounds that were synthesized displayed the ability to disrupt the interaction between PCNA and a PIP box-containing peptide. The IC50 values of these compounds had similar or improved affinity to that of T2AA, an established inhibitor of PCNA-PIP box interactions. The information gained here could be useful for subsequent drug lead candidate identification.","abstract_has_math":false,"creators":["Bartolowits, Matthew David"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation","degree_discipline":"Medicinal Chemistry and Molecular Pharmacology","degree_department":null,"school":null,"contributors":["Vincent J Davisson","Robert L Geahlen","Markus A Lill","Mark A Lipton"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2015,"date_issued":"2015-01-01T08:00:00Z","date_published":"2015-01-01T08:00:00Z","updated_at":"2026-07-24T03:54:17Z","subjects":["Epidermal Growth Factor Receptor","Fragment-Based Drug Design","Nuclear Targeting","Peptoids","Proliferating Cell Nuclear Antigen","Protein-Protein Interactions"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://docs.lib.purdue.edu/open_access_dissertations/1089","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Vincent J Davisson","Robert L Geahlen","Markus A Lill","Mark A Lipton"]},{"key":"dc:creator","label":"Author","values":["Bartolowits, Matthew David"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"thesis:degree_discipline","label":"Discipline","values":["Medicinal Chemistry and Molecular Pharmacology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Epidermal Growth Factor Receptor","Fragment-Based Drug Design","Nuclear Targeting","Peptoids","Proliferating Cell Nuclear Antigen","Protein-Protein Interactions"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://docs.lib.purdue.edu/open_access_dissertations/1089"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Integral to cell viability is the homotrimeric protein complex Proliferating Cell Nuclear Antigen (PCNA) that encircles chromatin-bound DNA and functionally acts as a DNA clamp that provides topological sites for recruitment of proteins necessary for DNA replication and damage repair. PCNA has critical roles in the survival and proliferation of cells, as disease-associated dysregulation of associated functions can have dire effects on genome stability, leading to the formation of various malignancies ranging from non-Hodgkin’s lymphoma to skin, laryngeal, ocular, prostate and breast cancers. Here, a strategy was explored with PCNA as a drug target that may have wider implications for targeting protein-protein interactions (PPIs) as well as for fragment-based drug design. A design platform using peptidomimetic small molecules was developed that maps ideal surface binding interaction sites at a PPI interface before considering detailed conformations of an optimal ligand. A novel in silico multi-fragment, combinatorial screening approach was used to guide the selection and subsequent synthesis of tripeptoid ligands, which were evaluated in a PCNA-based competitive displacement assay. From the results, some of the peptoid-based compounds that were synthesized displayed the ability to disrupt the interaction between PCNA and a PIP box-containing peptide. The IC50 values of these compounds had similar or improved affinity to that of T2AA, an established inhibitor of PCNA-PIP box interactions. The information gained here could be useful for subsequent drug lead candidate identification."]},{"key":"dc:title","label":"Title","values":["Discovery of Molecules that Modulate Protein-Protein Interactions in the Context of Human Proliferating Cell Nuclear Antigen-Associated Processes of DNA Replication and Damage Repair"]}]}],"canonical_facts":{"dc:contributor":["Vincent J Davisson","Robert L Geahlen","Markus A Lill","Mark A Lipton"],"dc:creator":["Bartolowits, Matthew David"],"dc:description.abstract":["Integral to cell viability is the homotrimeric protein complex Proliferating Cell Nuclear Antigen (PCNA) that encircles chromatin-bound DNA and functionally acts as a DNA clamp that provides topological sites for recruitment of proteins necessary for DNA replication and damage repair. PCNA has critical roles in the survival and proliferation of cells, as disease-associated dysregulation of associated functions can have dire effects on genome stability, leading to the formation of various malignancies ranging from non-Hodgkin’s lymphoma to skin, laryngeal, ocular, prostate and breast cancers. Here, a strategy was explored with PCNA as a drug target that may have wider implications for targeting protein-protein interactions (PPIs) as well as for fragment-based drug design. A design platform using peptidomimetic small molecules was developed that maps ideal surface binding interaction sites at a PPI interface before considering detailed conformations of an optimal ligand. A novel in silico multi-fragment, combinatorial screening approach was used to guide the selection and subsequent synthesis of tripeptoid ligands, which were evaluated in a PCNA-based competitive displacement assay. From the results, some of the peptoid-based compounds that were synthesized displayed the ability to disrupt the interaction between PCNA and a PIP box-containing peptide. The IC50 values of these compounds had similar or improved affinity to that of T2AA, an established inhibitor of PCNA-PIP box interactions. The information gained here could be useful for subsequent drug lead candidate identification."],"dc:identifier":["https://docs.lib.purdue.edu/open_access_dissertations/1089"],"dc:subject":["Epidermal Growth Factor Receptor","Fragment-Based Drug Design","Nuclear Targeting","Peptoids","Proliferating Cell Nuclear Antigen","Protein-Protein Interactions"],"dc:title":["Discovery of Molecules that Modulate Protein-Protein Interactions in the Context of Human Proliferating Cell Nuclear Antigen-Associated Processes of DNA Replication and Damage Repair"],"thesis:degree_discipline":["Medicinal Chemistry and Molecular Pharmacology"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T03:54:17Z"}