Optimalisering: Constructing therapeutic peptides for controlling host responses to bacteria

Serious infections can sometimes lead to a syndrome called sepsis, also referred to as blood poisoning. Sepsis is defined as physiologic changes in response to systemic inflammation that the infection is initiating. These changes consist of strong inflammatory- and coagulation activation that may lead to organ damage and death. Despite current treatment strategies and advances in supportive care of critically ill patients, the mortality rate has barely decreased during the past decades. Therefore, there is a need for identifying new targets and new strategies in treating septic patients. This invention is based upon novel data from our group showing that host responses to bacteria can be controlled by interfering with the endosomal Toll-like receptor 4 (TLR4) signalling pathway. We have identified interaction domains in two intracellular proteins that seem to be required to mount an inflammatory response towards Gram-negative bacteria. Based on these data we have constructed and optimized peptides that interfere with the interaction of these two proteins, and subsequently inhibit the inflammatory response. These anti-inflammatory peptides may form a new treatment strategy for preventing serious host reactions towards bacteria and virus. Results that we have obtained so far are very promising. Peptides that target these two interaction domains markedly shuts down both signaling pathways of TLR4. In a screening of amino acid substitutions of the anti-inflammatory peptides, we discovered that some substitutions had a marked toxic effect on hematological cancers. This observation has an innovation potential that was included in a revised patent application that was re-submitted in 2021.

Prosjektet bygger på publiserte resultater fra vår gruppe som viser at immunreseptoren SLAMF1 kan regulere Toll-lignende reseptor 4 (TLR4) sine proinflammatoriske effekter. Dette ga opphav til en ide om å lage peptider fra SLAMF1 som kunne hemme responser fra TLR4. Vi har lykkes med å konstruere slike peptider. Vi har avdekket de molekylære mekanismene for denne hemmende effekten. Vi oppdaget også at varianter av SLAMF1 peptidene har toksisk effekt på hematologiske kreftcelletyper. IP rettene er sikret gjennom en PCT patentsøknad. TTO-NTNU, sammen med oss, er nå i dialog med flere Biotek firma for eventuell lisensiering og videreutvikling av prosjektet. Prosjektet kan resultere i nye medikamenter for behandling av akutt- og kronisk inflammasjon.

Sepsis is a clinical syndrome defined by physiologic changes in response to systemic inflammation, which are likely attributable to an infection. In the presence of a systemic infection, microbial pathogens and their soluble mediators induce strong inflammatory- and coagulation activation, leading to hypercytokinemia, severe sepsis and septic shock. Despite current treatment strategies and advances in supportive care of critically ill patients, the mortality rate has barely decreased during the past decades. Therefore, there is a need for identifying new targets and new strategies in treating septic patients. This invention is based upon novel data from our group showing that host responses to Gram-negative bacteria can be controlled by interfering with the Toll-like receptor 4 (TLR4) signalling pathway. We have identified domains in two cytoplasmic proteins that interact, and this interaction seems to be required for mounting an inflammatory response towards Gram-negative bacteria. These two proteins are: Toll-receptor-associated molecule (TRAM) that is essential for TLR4 signalling, and SLAMF1 which is an immunoreceptor involved in innate and adaptive immunity. Based on our data we propose to construct and optimize peptides that interfere with the interaction of these two proteins, and subsequently inhibit TLR4-induced inflammatory responses. These anti-inflammatory peptides may form a new treatment strategy for preventing serious host reactions towards Gram-negative bacteria.