The emergence of multidrug-resistant infections is on the rise worldwide at an alarming pace underscoring the need for novel therapeutic agents. Self-assembling peptide nanotubes are a versatile class of synthetic supramolecular structures with considerable potential for addressing this urgent need. Several designed cyclic D, L-alpha-peptides have been shown recently to possess potent and selective in vitro and in vivo (mice) activities against multidrug resistant bacterial infections including vancomycin-resistant Enterococcus faecalis (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). We propose here a multidisciplinary research program that not only is aimed at further advancing new concepts in the design and use of functional peptide nanotubes, but also directed toward large-scale mapping of the scope and utility of this class of supramolecular structures as novel antimicrobial and anticancer agents. The scope of the proposed studies range from basic research endeavors in the design of capped transmembrane channels for use in stochastic sensing, design of photo-regulated transmembrane channels and tubular materials, to rational and combinatorial library approaches in the design, selection, and structure-activity relationship analyses of antimicrobial agents.
The specific aims of the proposed research program are: (1) Design, synthesis, characterization, and utility of capped transmembrane D, L-alpha-peptide nanotubes in stochastic sensing; (2) design and analysis of photo-regulated peptide nanotubes and transmembrane ion channels; (3) Design, synthesis, in vitro selection, and characterization of antimicrobial and cytotoxic self-assembling nanotubes from encoded single-bead combinatorial libraries of six- and eight-residue cyclic D, L-alpha-peptides; quantitative structure-activity analyses and biophysical characterizations for use in rational lead optimizations; in vivo (mice) efficacy, toxicology, pharmacokinetics, and bioavailability studies; and (4) design, synthesis, and characterization of amphiphilic beta3-cyclic peptide nanotubes and in vitro evaluation of biological activity, membrane selectivity, and biophysical characterizations.
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