Discerning the Therapeutic Potential of Peptoid-Based Mimics of Bioactive ProteinsPublic Deposited
Nature has been evolving innovative solutions to complex design challenges for billions of years, the success of which is evidenced by the myriad of life-sustaining systems that operate with unparalleled simplicity, efficiency, and durability. Biomimetic researchers derive inspiration from principles underlying natural phenomena to solve design challenges. This work is focused on the development of N-substituted glycines (peptoids) as functional mimics of bioactive proteins including antimicrobial peptides (AMPs) and lung surfactant (LS) proteins. Peptoids are synthetic, sequence-specific biopolymers that are well-suited for use in therapeutic applications; they exhibit a stable secondary structure similar to that of α-peptides, and their non-natural backbone renders them impervious to proteases. The ever-increasing rate at which bacteria evolve to effect multi-drug resistance has spurred research interest in novel antibiotic agents. Natural AMPs are ubiquitous components of innate immunity that have evolved to defend host organisms against a wide variety of pathogenic species. AMPs thwart the development of bacterial resistance because they employ a generalized mode of action, involving electrostatic and hydrophobic interactions with cellular membranes and intracellular targets. While the susceptibility of AMPs to proteases reduce their bioavailability, peptoid-based AMP mimics ("ampetoids") can circumvent this shortcoming. Here we explore three areas relevant to the therapeutic potential of ampetoids: selectivity, broad-spectrum activity, and in vivo efficacy. Structure-activity relationships reveal that selectivity is modulated in predictable ways by changes in physicochemical properties and subtle changes in sequence characteristics. Ampetoids were found to exhibit broad-spectrum activity, and we report the first demonstration of ampetoids reducing bacterial counts in vivo. Lung surfactant, comprised of lipids and surface-active proteins, reduces surface tension at the alveolar air-liquid interface to enable normal breathing. The absence or dysfunction of LS leads to respiratory distress syndrome. While animal-derived surfactants are commonly used to treat neonatal RDS, the development of a wholly-synthetic LS replacement formulation would afford distinct advantages discussed herein. Here we report that peptoid-based mimics of the surfactant proteins SP-B and SP-C interact synergistically to reduce surface activity in vitro. Moreover, we present studies using two animal models of RDS, which suggest that peptoid-enhanced LS replacements can mitigate some symptoms of the disease.