Transforming an innate structural fold into a drug targeting TLR-driven systemic inflammation

Excessive activation of Toll-like receptors (TLRs) due to unresolved infection and inflammation leads to destructive diseases, such as sepsis.

Current treatments based on antibiotics target bacteria only, and not the accompanying over-activation of immune responses.

Therefore, there is an urgent and unmet need for new innovative treatments.Thrombin derived C-terminal peptide (TCPs) are known to target both bacteria and the resulting TLR-mediated inflammatory response during infection.

Inspired by the structure and mode of action of these evolutionary old TCPs, we here investigate the mode of action in vitro and in vivo of new peptide-based drug class (TraP) targeting TLRs.The complete 4-year proposal includes basic studies for pre-clinical development of TraP as systemic drug.

Using a combination of structure-based design, nuclear magnetic resonance spectroscopy, crystallography, biophysical, biochemical, mass spectrometry, transcriptomic, microbiological, cellular, and in vivo studies, we will have a complete picture of the effects of TraP in vitro and in vivo.

This will provide a basic understanding of their efficacy, which is necessary for future preclinical and clinical studies.Identification and deep characterization of molecules targeting TLRs will have significant implications for the future prevention and treatment of infections and the related inflammatory process, of high relevance for wound infections, other infective-inflammatory conditions, and sepsis.