Date of Completion

Spring 5-1-2022

Thesis Advisor(s)

Brian Aneskievich

Honors Major

Doctor of Pharmacy

Disciplines

Other Pharmacy and Pharmaceutical Sciences

Abstract

Tumor necrosis factor α-induced protein 3-interacting protein 1 (TNIP1) is a negative regulator of inflammatory signaling in several diseases. TNIP1 is also an intrinsically disordered protein (IDP), which makes it difficult for current drugs to affect it. More research on IDPs could lead to novel drugs targeting TNIP1, leading to improved therapies for patients with acute and chronic inflammatory diseases. The main difference between IDPs and the more common ordered proteins is that IDPs are flexible, a characteristic of TNIP1 which was demonstrated in this study via protease sensitivity. Ordered proteins are rigid, which means that they only have one well-defined three-dimensional structure. The flexibility of IDPs allows them to have multiple conformations that they can switch between quite easily. However, switching between conformations makes it much harder to solve for the structure of an IDP. Since developing drugs relies heavily on knowing a protein’s structure, IDPs have not yet been common therapeutic targets. Several screening approaches for new IDP-targeting drugs are considered here, including those driven by artificial intelligence. There have been some reports of successful small molecule screens, but finding a universal technique is still in high demand. Currently, it is thought that drugs binding to multiple conformations of IDPs may be beneficial over a drug only binding a single conformation. Since 20-30% of the proteins in our body are IDPs, continued characterization of IDPs could lead to better drug designing methods, more structural information about TNIP1, and a better multifaceted approach for treating psoriasis, cancer, Parkinson’s disease, ischemic vascular diseases, and beyond.

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