Dysregulation of the immune system is the underlying cause of potentially fatal conditions such as sepsis and severe allergic reactions. Adequate therapies are currently absent or lacking. There is therefore an unmet medical need for therapies that would target the underlying causative immune pathways.
Anti-microbial peptides (AMPs) possess promising anti-inflammatory activities, however, are commonly toxic.
In a series of newly synthesized peptides, the outlined invention provides a method to modify naturally occurring AMPs to possess both potent therapeutic anti-inflammatory activity and minimal toxicity in-vitro and in-vivo.
The resulting series of peptides were shown to remarkably inhibit severe allergic reaction as well.
- Novel Therapy for sepsis and severe allergic reactions
- Very potent anti-inflammatory and anti-allergenic agents
- Targeted against the underlying cause of both indications, which is an improper and uncontrolled immune response
- Diversity elucidating the parameters that control efficiency and toxicity allows to modify the basic formula to optimally fit different systems
With natural AMPs properties in mind, Prof. Shai and his team characterized the key modifications that underline anti-inflammatory activity and toxicity. A series of peptides with variable degrees of hydrophobicity, length, charge, position of charge and amino acid chirality were tested for their LPS neutralizing activity.
It was found that ~20mer peptides under the formula Kn(AL)mKn (wherein n et each occurrence is independently 0-2, and m is 6-9) demonstrate anti-inflammatory activities at nanomolar concentrations as evident by inhibition of TNF? secretion from macrophages, following LPS induction. Furthermore, a single dose of an exemplary peptide was able to inhibit septic shock in mice induced by purified LPS or by whole heat-killed E.coli.
In contrast to previous attempts, which focused on increasing hydrophobicity, the core of the present invention is the designation of an optimal hydrophobicity that is necessary for high activity and low toxicity. Additional important features for LPS neutralizing were found to be ?-helical structure and strong oligomerization ability.
Surprisingly, the present peptides were shown to contain highly potent anti-allergenic activity as well. In-vitro inhibition of Fc?RI-mediated degranulation was recapitulated in-vivo