The innate immune system is the first line of defense against host infection, and combats a variety of pathogens, including bacteria. A prominant component of the innate immune system, Toll-like receptors (TLRs) are evolutionarily conserved type I transmembrane proteins critical for initiation of the innate immune response to these invasive pathogens. Current opinion speculates that TLR signaling may interplay with other innate immune components, including that of antimicrobial peptides. Antimicrobial peptides (AMPs) are host-defense agents capable of both bacterial membrane disruption and immunomodulation. While diverse in structure and sequence, AMPs are often short and amphipathic.<br/><br/>Here we discuss the family of AApeptides, peptidomimetics with an atypical peptide backbone. AApeptides were designed to mimic the characteristics of endogenous AMPs, and have potent antibacterial activity against clinically relevant Gram-positive and Gram-negative bacteria, many of which are resistant to conventional antibiotics. Interestingly, they also harness the immune response and inhibit lipopolysaccharide (LPS) activated Toll-like receptor 4 (TLR4) signaling, suggesting that AApeptides have dual roles as novel antimicrobial and anti-inflammatory agents. We show that AApeptides inhibit TLR-induced signaling in nitric oxide production, NF-κB activation, and cytokine release. Additionally, these peptides are not toxic in mammalian cells at concentrations at least thirty times that of the IC<sub>50 </sub>value.

Peptidomimetics as dual function antimicrobial and anti-inflammatory agents

249th National Meeting (2015)

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