Project Summary For a wide range of diseases, peptides could provide immense therapeutic benefit, however the short half-lives of peptides in biological environments hinder their translation to clinical use. Immune system-mediated clearance, renal filtration of structures smaller than 20 nm (such as peptides), and enzymatic degradation all contribute to the short half-lives of peptides. Conjugating peptides to polymers can overcome many of these obstacles and prolong half-life, similarly as in the case of PEG-INTRONTM, a star-shaped polymer decorated with the protein therapeutic interferon alfa-2b that prolongs half-life of the protein and enables its use to treat cancer and hepatitis, among other conditions. However, conjugation of peptides to polymers may also detract substantially from the therapeutic function. For example, attachment of an antimicrobial peptide to one end of a polymer reduces toxicity to mammalian cells, but also markedly reduces antimicrobial activity. On the other hand, attaching multiple antimicrobial peptides to a polymer chain can improve activity by enabling multivalent interactions of peptides with biological targets (e.g., pathogenic microbes), but may also cause undesired toxic effects to mammalian cells. The overall goal of this proposal and a major thrust of my research group is to leverage advances in polymer chemistry that enable precision control of polymer composition, molecular weight, architecture, and supramolecular assembly to optimize presentation of therapeutic peptides. By varying the density and number of peptides pendent to a water-soluble polymer chain, we aim to maximize the function and therapeutic benefit of peptides designed to combat infectious disease and Amyotrophic Lateral Sclerosis. One set of conjugates will feature antimicrobial peptides, and another will feature peptides we designed to bind and sequester toxic poly(dipepetide)s implicated in Amyotrophic Lateral Sclerosis via stereochemistry-driven interactions. We will characterize the size, morphology, surface charge, and stability of the polymer-peptide conjugate variants, and interactions with biological targets to connect conjugate structure to these therapeutically relevant biophysical properties. In other situations, chemical modification of peptides in any arrangement can abrogate the intended function; in these cases, physical encapsulation of the peptides within polymer particles provides an excellent alternative. By modulating both the percentage and arrangement of charge-neutral groups in otherwise anionic polymers, we aim to control the stability, as well as the loading and release rates of cationic therapeutic peptides. Together, these studies will provide critical insight regarding formulating peptides with polymers to optimize therapeutic function and thereby accelerate the clinical implementation of this important class of therapeutics.