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Antimicrobials by immune stimulation

Final Report Summary - AMIS (Antimicrobials by immune stimulation)

The ultimate aim of the AMIS project was to use the strength of the human innate system to design antimicrobial drugs for future generations. Considering the fact that antimicrobial proteins in the human immune system are often combined with inflammatory signals in one single molecule, AMIS would implement that same approach and reshuffle different parts of different molecules to make novel effector molecules that would still have these combined functions but would be optimally adapted for therapeutic intervention. Furthermore, taking into consideration that within the innate immune system many molecules were identified over the last years that were involved in direct or indirect clearance of bacteria, the consortium selected the most promising and innovative compounds with this dual mode of action and set out to:
- design proteins with anti-microbial activity in combination with an inflammatory trigger and target extra cellular bacteria;
- design proteins with inflammatory priming capacity (without extra anti-microbial activity) and target intracellular bacteria;
- discover new modulators to dampen inflammation.

The project focused on optimising and validating various in vitro and ex vivo (whole-blood) assays for the measurement of phagocytosis, oxidative burst and microbial killing. This offered important tools for the evaluation of the anti-microbial properties of the proteins isolated. Furthermore, while working on the interface between microbes and innate immunity, several novel compounds with either anti-microbial or anti-inflammatory activity were identified. Amongst these, Toll-like receptor (TLR) inhibitors, novel and specific complement inhibitors, as well as a novel cathelicidin-like antimicrobial. Of crucial importance was the identification of the exact molecular mechanism of action of several compounds such as of the Acid sphingomyelinase (ASMase), lipocalin-2, Formyl-peptide receptor-like 1 (FPRL1) and others, as well. The project also focused on selecting several of the molecules to build a better-than-nature fusion compound that would prove that the combination of the characteristics of these molecules, where microbes and innate immunity meet, would be beneficial in combatting infections in the future. The first fusion compound that combines structural features from both human surfactant protein D and human cathelicidin LL-37 was defined.

As anticipated the research over this three-year period did not result in a ready-to-use protein therapeutic. In fact, a lot on truncated versions of proteins became known and conclusion was that the ideal at the start of this project was still very far away. The reason for that was not technical. It is more-or-less the standard technology to make such proteins. It is the basic lack of knowledge of function and structure and especially the interaction between these areas that forms the basis of why it is not possible to design proteins that would fulfil functions that yet do not exist yet.

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