Investigation of the mechanism of action and the therapeutic potential of peptides derived from the vaccinia virus protein A46

Abstract

The innate arm of the mammalian immune system employs a number of pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), which recognise pathogen associated molecular patterns (PAMPs) and initiate inflammatory responses. TLRs signal via homotypic interactions between their cytoplasmic Toll-IL-1 receptor (TIR) domains and TIR domain- containing adaptor proteins. Over the course of evolution most viruses developed various immune evasion strategies, one of which involves inhibiting PRR signaling pathways in order to avoid immune detection. Thus, Vaccinia virus (VACV) encodes the A46 protein, which binds to TIR-domain containing proteins ultimately preventing TLRs signalling (Stack et al., 2005). Many viral proteins are muhifunctional and likely to target host proteins using evolutionary optimized binding surfaces. In this project an 11-amino acid long peptide from A46 protein has been identified, which when fused to a cell-penetrating delivery sequence potently inhibited multiple TLR4-mediated responses. The peptide was found to be TLR4- specific, while inert towards other TLRs, and therefore was termed Viral Inhibitory Peptide of toll-like Receptor 4 (VIPER). VIPER was active in murine cells and in vivo, where it inhibited LPS-induced IL-12p40 secretion. Also, in contrast to another previously described viral peptide P13 (McCoy et al., 2005), VIPER potently inhibited LPS-induced cytokine production in primary human cells.