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. We have shown that 6- and 8-residue cyclic D, L-alpha-peptides can 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). The supramolecular approach has also been applied to the design and discovery of a new class of broad- spectrum antiviral agents. An 8-residue cyclic D, L-alpha-peptide has been shown to specifically prevent the development of low pH in endocytic vesicles, arrest the escape of virions from the endosome, and abrogate virus infections without an apparent adverse effect on cell viability. The proposed studies are aimed at further advancing the fundamental design aspects as well as practical biomedical applications of self-assembling peptide nanotubes. The scope of the proposed studies range from the design of novel heterocyclic alpha,epsilon- and alpha,beta-cyclic peptide nanotubes, metal ion-dependent systems, glycopeptides, and prodrug concepts to rational and combinatorial library approaches directed at the design and discovery of new classes of antiviral and antibacterial agents.
The specific aims of the proposed research program are: (1) Design, synthesis, and characterization of novel self-assembling peptide nanotubes based on cyclic alpha, beta-, and alpha, epsilon-heterocyclic peptide backbone architectures. (2) Design, synthesis, and characterization of metal ion-dependent self-assembling cyclic D,L-alpha-peptide nanotubes and their utility in the design of Ca2+dependent membrane active species and antibacterial agents. (3) Investigate prodrug design concepts based on backbone N-alkylated antibacterial cyclic D, L-alpha-peptides. (4) Assess the utility of Ser (beta-GlcNH2) as the cationic amino acid in the design of membrane-active antibacterial cyclic D, L-alpha- glycopeptides. (5) Design, synthesis, selection, and characterization of antibacterial and antiviral self- assembling cyclic peptides, including the use of directed combinatorial libraries of cyclic D, L-alpha-, D, L-alpha- glyco-, and alpha, beta-peptides; establishment of a comprehensive data set for quantitative structure-activity relationship analyses; exploring synergistic activity of cyclic D, L-alpha-peptide binary mixtures; and in vivo efficacy, toxicity, and pharmacokinetics of selected antibacterial cyclic peptides.
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