Sunday, October 6, 2024
10/6/2024
Streamlining PPI Inhibitor Discovery via Chemically Enhanced Phage Display Project Summary Protein-protein interactions (PPIs) are increasingly recognized as rewarding targets against which powerful therapeutic drugs can be devised. This is perhaps best demonstrated by the remarkable success of the series of anti-PD-1/PD-L1 antibody drugs developed to treat cancer. Despite the excitement, antibody-based drugs do have a few limitations, including modest stability, lack of oral availability, poor tissue penetration and inability to reach intracellular targets. Nevertheless, small molecule based PPI inhibitors remain scarce as large PPI interfaces cannot be efficiently blocked by small molecule drugs. The shortcomings of these two major drug modalities towards PPI inhibition rekindled people’s interest in peptides as an alternative modality. Peptides, as a quintessential example of medium-sized molecules, would be able to forge large enough molecular contact to block a PPI interface. On the other hand, they hold promise to overcome the limitations of antibody drugs, particularly in terms of oral availability. The enthusiasm in peptide drugs was further fueled by the advent of genetically encoded screening platforms such as phage display, which enables rapid screening of peptide libraries. However, phage display often fails to reveal PPI inhibitors of desired potency, presumably due to the overly simplistic structures of natural peptides in contrast to peptide natural product-based drugs. Over the past few years, our group have made a number of exciting advances towards expanding the chemical space of phage display libraries. First, we have developed novel warheads that elicit reversible covalent binding of amines such as a lysine side chain. Second, we have successfully constructed covalent binding phage libraries and demonstrated their utility in PPI inhibitor discovery. Third, we have developed highly efficient chemistries for phage modification to give backbone rigidified peptide macrocycle libraries. These advances pave the road for the further exploration of phage libraries of complex structured peptides. With this MIRA application, we seek to develop novel phage libraries that display various covalent warheads and/or backbone rigidifying elements. These phage libraries will be assessed for PPI inhibitor discovery against a panel of model proteins as well as proteins that enable bacterial immune evasion or confer antibiotic resistance. Our proposed research will allow, for the first time, pharmacologic interrogation of host-pathogen PPIs as potential targets of novel antibacterials. Importantly, the proposed work will yield a powerful platform for discovering non-antibody based PPI inhibitors, which will have broad impact far beyond the scope of this proposal.
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