Science & IP
The SCHOOL drug discovery science
Cells express multiple surface receptors that respond specifically to individual stimuli. Multichain immune recognition receptors (MIRRs) are membrane receptors with their binding and signaling domains located on separate subunits. Inhibition of MIRRs is a promising strategy to prevent and treat a variety of serious disorders. Examples are lung, breast and other cancers, sepsis, hemorrhagic shock, empyema, rheumatoid arthritis, diabetes, heart disease, stroke, Crohn’s disease, and other inflammatory and immune diseases. Current approaches are to block binding of cognate ligands to receptors by using large protein molecules such as monoclonal antibodies or soluble receptors and often have serious off-target and side effects.
SignaBlok’s innovative approach does not interfere with ligand binding and sets the stage for the development of new and disruptive therapies.1,2 This approach is based on our novel model of receptor signaling, the Signaling Chain HOmoOLigomerization (SCHOOL) model, that solves the long-standing puzzle of transmembrane signal transduction at the level of protein-protein interactions – processes that can be influenced and controlled. 3,4 The model reveals intrareceptor transmembrane interactions as universal therapeutic target. 2 This allows the rational design of receptor-specific peptide therapies for disorders mediated by any member of the MIRR family. 2
As drug candidates, peptides possess several competitive advantages over large protein molecules including: (1) lower manufacturing costs, (2) higher activity per mass, (3) lower royalty stack because of a simpler IP landscape during discovery and manufacturing, (4) greater stability, (5) less chance of unintended interaction with the immune system, and (6) better organ or tumor penetration.
Importantly, in order to establish a successful infection, different viruses such as HIV, CMV, and others, have evolved the SCHOOL-like mechanisms to inhibit receptor signaling and enter the host cell without triggering the immune response.5 Viruses represent millions years of evolution and the efficiency and optimization that come along with it. SignaBlok takes advantage of this billion-year development process and transfers it to therapeutic strategies that require similar functionalities.5
Macrophage-targeted delivery of therapeutics and imaging agents: The science behind it
Lipoproteins transport lipids like cholesterol and triglycerides within the water-based bloodstream in a human body. Lipoprotein-like nanoparticles are emerging as important vehicles to transport therapies and diagnostics. These multifunctional nanoparticles can be designed and synthesized as discoidal or spherical particles, with hydrophilic or hydrophobic inner core. SignaBlok’s proprietary technology converts these particles into a substrate to macrophages. This is advantageous for purposes of diagnosis or targeted treatment because after administration, most of these particles get bound and/or uptaken by macrophages.
SignaBlok’s integrated nanosystems can deliver therapies and imaging agents directly to macrophage-rich sites of disease such as tumor-associated macrophages or vulnerable atherosclerotic plaques. Because of their high targeting specificity, these nanoparticles significantly increase local concentration of agent, improve its therapeutic or imaging efficacy, diminish systemic toxicity, and reduce dose. This flexible multifunctional nanoplatform also has high potential in image-guided therapy approaches.
SignaBlok’s extensive IP portfolio covers a broad range of methods and compositions to diagnose, treat and prevent multiple large market indications with unmet needs. It also covers optimization principles with respect to receptor-specific peptide inhibitors as well as approaches to high throughput screening of receptor-specific inhibitory small molecules.
- Sigalov AB. Immune cell signaling: a novel mechanistic model reveals new therapeutic targets. Trends Pharmacol Sci 2006; 27:518-524.
- Sigalov AB. New therapeutic strategies targeting transmembrane signal transduction in the immune system. Cell Adh Migr 2010; 4:255-267.
- Sigalov AB. Multichain immune recognition receptor signaling: different players, same game? Trends Immunol 2004; 25:583-589.
- Sigalov AB. The SCHOOL of nature. I. Transmembrane signaling. Self/Nonself 2010; 1:4-39.
- Sigalov AB. Novel mechanistic insights into viral modulation of immune receptor signaling. PLoS Pathog 2009; 5:e1000404.