Macrocyclic peptide inhibitors of viral fusion proteins

Abstract

Pandemic outbreaks of viruses present a significant global challenge, necessitating continuous updates to vaccines and exploration of new antiviral drugs. This thesis explores a strategy targeting the coat glycoproteins of two pandemic viruses to discover new broadly active antiviral drugs. The focus is on viral fusion proteins and cyclic peptide selection systems, emphasizing the need for innovative approaches due to emerging drug resistance. The RaPID system, which uses mRNA display and in vitro translation is used to screen for antiviral cyclic peptides. In chapter 2, the RaPID system is used to identify macrocyclic peptide inhibitors against Influenza A hemagglutinin (HA) protein. Peptides targeting the HA stem showed broad activity against H1 and H5 subtypes, demonstrating the RaPID system's effectiveness. In chapter 3, in order to address resistance, the study identifies peptides that inhibit a mutant HA protein resistant to earlier inhibitors. Combining peptides forces the virus to develop mutations that compromise its fitness, suggesting a potential strategy to counteract resistance. In chapter 4, the research discovers peptide inhibitors for SARS-CoV-2. Peptide S1b3inL1 exhibits significant inhibition across multiple variants and related viruses. The peptide likely inhibits infection by stabilizing the prefusion form of the spike protein, a novel approach to counteracting the virus. This thesis highlights the potential for cyclic peptide inhibitors to target various viral fusion proteins and the importance of developing broad-spectrum inhibitors to address unpredictable viral mutations. Future work could focus on iterative selection processes, optimization techniques, and studying resistance mechanisms to enhance the clinical potential of discovered inhibitors. Overall, this research underscores the strength of the RaPID system in finding new peptide inhibitors and overcoming viral resistance, offering promising leads for further drug development.