- Antimicrobial Peptide Stabilization and Natural Product Scaffold Mimicry Using Triazolinedione-Based Cyclization Methods
Antimicrobial peptides (AMPs) are a promising, yet underdeveloped class of therapeutics with structural characteristics that go beyond traditional drug discovery guidelines. Though structurally diverse, most AMPs have defined peptide secondary structures that promote their mechanisms of action. A common hypothesis is that the stabilization of these peptide secondary structures may enhance their biological properties. The main goals of this project involve the development and application of a selective cyclization reaction to stabilize and mimic the cyclic structures of these bioactive peptides. Triazolinediones (TADs) are reactive molecules with remarkably selective chemical reactivity that have enabled applications in organic synthesis, chemical biology, and medicine. Substituted TADs are used for tyrosine-selective bioconjugation reactions that satisfy ‘click reaction’ chemical requirements. TAD-containing peptides can react selectively with tyrosine (Tyr) to yield TAD-Tyr linked cyclic peptides. Toward antimicrobial peptide therapeutic discovery, I will use TAD-based cyclization methods to stabilize and mimic the structures of the bioactive peptides magainin and arylomycin. The magainins are naturally produced helical AMPs isolated from the African clawed frog that exhibit Gram-negative antimicrobial activity. Using an electrochemical oxidation method I will prepare a series of structure-stabilized magainin peptides and evaluate their biological properties. The naturally produced arylomycin AMPs are structurally defined by a smaller, biaryl-linked cycle. Here I will use on-resin TAD-based cyclization chemistry to prepare a close mimic of the biaryl-linked cycle. Long-term, the development of TAD-based cyclization methods for the stabilization and mimicry of peptide secondary structures could expand future access to stable peptide therapeutics.