Novel immunosupressive peptides, derived from the TM domain of the HIV protein gp41, with high selectivity towards distinct immune cell populations.
Uncontrolled activity of immune cells is an underlying cause of both autoimmune and inflammatory diseases. One of the major challenges in the field is to develop therapeutics that would target specific populations of immune cells, in order to avoid immune-deficiencies that would leave patients exposed to infections.
The present invention provides novel peptides, based on Immunosupressive regions within the TM domain of the HIV gp41 fusion protein. These peptides were shown to specifically and efficiently inhibit T-cells and TNF? secretion from inflammatory macrophages. Importantly, these peptides were shown to have particular inhibitory effects towards T cells that are activated in a multiple sclerosis model.
- Selective therapy towards T cell mediated autoimmune diseases (e.g. multiple sclerosis)
- Selective therapy towards TNF?-associated inflammatory disorders
- Specific towards defined cell populations avoids general immune suppression
- Significant efficiency towards MS-associated T-cell activation
The present invention takes advantage of the potent immune evasion mechanisms that are utilized as part of the HIV virus pathogenesis. Gp41, a component of the virus envelop, is a transmembrane glycoprotein that mediates viral entry into cells of the immune system. In addition to its role in mediating the actual fusion event, gp41 has been shown to contain immunosuppressive activities that are attributed to its N terminus.
Using biochemical and biophysical approaches, Prof. Shai and his team from the Weizmann institute, reveal yet another immunosuppressive activity of gp41, exerted via its transmembrane domain. Importantly, this immunosupressive activity was shown to be specific for T cell activation (mediated through binding to CD3/TCR complex) and Toll-Like Receptor (TLR)-mediated activation of macrophages.
The present inventors generated synthetic peptides that derive from the gp41 trasmembrane domain and demonstrated their suppressive activity in both in-vitro and in-vivo models.
Significantly, T-cell activation was inhibited following activation with a peptide associated with the propagation of multiple sclerosis (MOG 35-55), proposing a specific inhibitory activity towards MS-generating mechanisms. Macrophages inhibition was shown to significantly compromise the secretion of pro-inflammatory factors, predominantly TNF?, following LTA (lipotechoic acid) activation.