Computational methodologies have been developed for the design of biomimetic polymers that 1) mimic key biological properties of proteins and 2) are more stable and inexpensive to produce than natural proteins. The first application of this technology has been the design and synthesis of non-peptidic mimics of host defense peptides that play a critical role in health, serving as a first line of attack against a wide range of microbes. The host defense peptides commonly exert their antimicrobial effect by damaging the bacterial membrane, sparing eukaryotic cells because of inherent differences in membrane cytoarchitecture. These peptides are potentially exciting therapeutic agents because of their broad spectrum of activity, rapid bactericidal activity and very low incidence of development of bacterial resistance. However, significant pharmaceutical issues, including systemic toxicity and difficulty and expense of manufacturing, have severely hampered clinical progress. Therefore, we have recently developed nonpeptidic antimicrobial polymers and defined-length oligomers that are safe, have broad and potent antimicrobial activity, and are easy and inexpensive to synthesize. Importantly, because these compounds mimic the structure and biological activity of host defense peptides, the appearance of bacterial resistant strains is very unlikely to occur. Presently, eight classes of polymer and oligomer compounds have been synthesized and tested for antimicrobial activity. From a small library of approximately 150 compounds, several compounds have been identified that have broad and potent antimicrobial activity against a panel of gram positive and gram negative bacteria, including antibiotic-resistant strains. For several of the compound classes, structure/activity relationships for potency and selectivity for bacterial vs. mammalian cell cytotoxicity have been elucidated. The goal of the Phase I studies is to begin the evaluation of the pharmaceutical potential of the oligomers under study to identify compounds or compound classes that demonstrate antimicrobial efficacy in vivo without obvious toxicity. The proposed studies for Phase I involve moving two potent oligomers selectively cytotoxic for bacteria through a series of pilot in vitro and in vivo assays to evaluate efficacy in an animal model of systemic infection. Results from these Phase I discovery lead studies will be used to focus on specific compound classes in Phase II to select development lead compounds for thorough lead optimization and development. ? ?
| Dawson, Michael John; Scott, Richard W (2012) New horizons for host defense peptides and lantibiotics. Curr Opin Pharmacol 12:545-50 |
| Scott, Richard W; DeGrado, William F; Tew, Gregory N (2008) De novo designed synthetic mimics of antimicrobial peptides. Curr Opin Biotechnol 19:620-7 |
