Conventionally, small molecule therapeutics have targeted well-defined, ligand-binding pockets, such as those offered by enzymes and cell surface receptors.1 In contrast to the clearly distinguishable pockets of enzymes, the contact surface between proteins and their biomolecular partners is often large and shallow, making them generally unattractive for drug design.2-4 However, the entire interfacial surface of protein-protein interactions (PPIs) may not be required for partner recognition, but may be facilitated by a small subset of contacting residues.5-8 These residues--referred to as hot spots--are frequently found organized on local folded segments known as secondary structures. Synthetic molecules that reproduce vital elements of secondary structures important for protein partner recognition can potentially inhibit chosen interactions leading to manipulation of fundamental processes controlled by PPIs.
Currently, there are two main classes of therapeutic agents--the "drug-like" small molecules (< 500 g/mol) and biologics (> 5000 g/mol). Small molecules have dominated the market due to low production costs, oral bioavailability, and stability. Biologics are regarded for their high potency and selectivity. In recent years, there has been an increased interest in the development of compounds that bridge the gap between these two categories to combat the promiscuity of small molecules and the poor pharmacokinetics of biologics, aiming to gain the benefits of both approaches. Peptide-based therapeutics offer diverse scaffolds that can be specifically tailored to antagonize targets of interest.
Chapter 1 introduces small and medium-sized molecules that have been shown to inhibit protein interactions containing helices at the interface. The small molecules act as functional space mimetics, while the medium-sized compounds encompass stabilized helical or foldamer. In vivo efficacy of both classes is compared. Chapter 2 addresses the development of a systematic method to choose new "druggable" targets and determine appropriate synthetic inhibitory ligands. We surveyed the Protein Data Bank (PDB) to identify multiprotein complexes, specifically those with helices at the interface that contribute to partner recognition. By categorizing these helical PPIs, we have determined that some protein complexes are potentially amenable to inhibition by small molecules, while others may require larger inhibitors. With this in mind, we designed two protein domain mimetic strategies--helix stabilization and helix surface mimetics. Chapter 3 assesses hydrogen bond surrogates (HBS) as in vivo modulators of hypoxia-induced signaling leading to a decrease in tumor progression. In the next chapter, rationally designed low-molecular weight oxopiperazine helix mimetics (OHM) mimicking the same helix as the HBS described in the previous chapter. Employment of two scaffolds for targeting of the same protein allows for a direct comparison of small and medium-sized molecules as protein antagonists. Chapter 5 discusses the incorporation of our OHM design into Rosetta, allowing for a streamline approach for the discovery of potent protein domain mimetics as inhibitors of protein-protein interactions.
|Advisor:||Arora, Paramjit S.|
|Commitee:||Bonneau, Richard, Mahal, Lara, Schlick, Tamar, Weck, Marcus|
|School:||New York University|
|School Location:||United States -- New York|
|Source:||DAI-B 76/01(E), Dissertation Abstracts International|
|Subjects:||Biochemistry, Organic chemistry|
|Keywords:||Hypoxia, Peptides, Protein-protein interactions, Small molecules, Transcription, Xenografts|
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