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

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.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Medicinal Chemistry and Molecular Pharmacology

Year

2015

Author dc:creator

• Bartolowits, Matthew David

Contributors dc:contributor

• Vincent J Davisson
• Robert L Geahlen
• Markus A Lill
• Mark A Lipton

• Epidermal Growth Factor Receptor
• Fragment-Based Drug Design
• Nuclear Targeting
• Peptoids
• Proliferating Cell Nuclear Antigen
• Protein-Protein Interactions

Repository record dc:identifier

https://docs.lib.purdue.edu/open_access_dissertations/1089

OAI identifier oai:identifier

oai:docs.lib.purdue.edu:open_access_dissertations-2305