Advantx’s SIGMA platform focuses on the development of disease-modifying therapeutics targeting Sigma chaperones and related proteins based on small molecules with novel chemical structures precisely designed to modulate specific pathways and restore interorganelle signaling, cellular homeostasis, and multilevel proteostasis.
Sigma receptors unlike any traditional receptor are ligand-operated chaperones and do not display homology to any other known mammalian protein. To solve their extraordinarily complex pharmacology we have developed the proprietary SIGMA platform, driven by AI-assisted computation, genetic analysis and multiple cell and animal models, is the basis on which we have designed in-house a broad portfolio of novel small molecules (new chemical entities) targeting the pluripotent Sigma-1 and Sigma-2 proteins, and other associated proteins, in a selective (single target), bispecific (dual symmetric) or biased (dual asymmetric) manner, acting as full or partial agonists (activators), antagonists (blockers) or allosteric (non-competitive) modulators of specific disease-causing pathways, while maintaining their ability as key chaperones to restore protein and cellular homeostasis in the living system.
The extraordinary precision with which these small molecules act inside cellular organelles by binding to specific parts of Sigma chaperones to modulate specific pathways in the manner required by the physiology of the identified disorders with genomic precision dramatically maximizes effectiveness, reducing unwanted off-target effects while promoting proteostasis balance, of the disease-modifying monotherapies developed by Advantx. Therapeutics whose efficacy and safety have been proven in multiple trials in knockout and transgenic murine models, identifying biomarkers that ensure translatability, progressing rapidly to become multi-supported pharmaceutical-grade drug candidates following stringent quality controls to ensure their safety before reaching patients.
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Sigma receptors and associated proteins:
The Sigma-1 receptor (σ1R), is a 223 amino acid-long, 26 kDa, ubiquitously expressed, pluripotent transmembrane protein coded by the gene SIGMAR1 on chromosome 9p13, and the unique ligand-operated chaperone in the central nervous system, localized in the endoplasmic reticulum (ER) at the contact zones with mitochondria (MAMs), a quasi-synaptic structure that controls proteostasis, cell death pathways, and mitochondrial bioenergetics. Sigma-1 exhibits a trimeric structure, with each receptor in the trimer having a single transmembrane domain that anchors it to the cytosolic side of the endoplasmic reticulum. The C-terminal half of the molecule is thought to be responsible for the chaperone activity. The N-terminal half in association with the lysosomal fusion complex factor, plays an important role in the regulation of protein synthesis and transport, protein folding and quality control, lipid and steroid synthesis, ion channel regulation, response to oxidative stress, carbohydrate metabolism, and calcium storage. The sigma-1 receptor being evolutionarily more closely related to fungal enzyme sterol isomerase than to mammalian neurotransmitter receptors indicates a fascinating aspect of the evolutionary biology of chaperones and its ability to rearrange the structure of molecules without changing its atomic composition. Sigma-1 interacts with other known ER chaperone proteins, including Immunoglobulin binding protein (BiP/HSPA5), Protein Disulfide Isomerase (PDI), and Calnexin. Defined as a multi-functional protein working also as an inter-organelle signalling modulator, it has the ability to re-localize to the ER network and cell membrane upon ligand-mediated or stress-induced stimulation, where it interacts with NMDARs. Sigma-1 can also translocate to the envelope of the nucleus where it binds to the inner nuclear envelope protein emerin and recruits several chromatin-remodelling factors to regulate gene transcription and restore protein homeostasis. As an inter-organelle signaling modulator, σ1R interacts with numerous proteins, including KCNA2, a potassium-gated channel key for neuronal and cardiovascular function, and DRD2, the dopamine receptor correlated with motor control and Parkinson’s disease, while connections with ITPR1 and ITPR3 link σ1R to calcium signaling pathways. Additionally, Sigma-1 associates with proteins involved in cholesterol synthesis, such as MSMO1, C14orf1, SQLE, and TM7SF2, as well as CYP51A1, which is essential for steroid hormone metabolism. Sigma-1 also interacts with endogenous ligands such as sphingosine, N, N-dimethyl sphingosine (DMS), dehydroepiandrosterone (DHEA), N-dimethyltryptamine (DMT), progesterone, and pregnenolone, and a variety of non-opiate compounds, accounting for the multi-faceted functions exerted by Sigma-1 in different tissues in health and disease. Sigma1 has the ability to organize in an oligomeric form, clustering in micrometer-sized cholesterol-enriched microdomains in the endoplasmic reticulum. The activation of Sigma-1 results in the disassembly and remodelling of σ1R microdomains in the ER, leading to a rapid release of mature proteins that are trapped in these microdomains, reducing protein aggregation, stimulating neurotrophin receptor signalling, enhancing autophagy, and stabilizing protein homeostasis (proteostasis), resulting in a robust response to stress and in neuroprotective effects. Sigma-1 activation also enhances the expression of CD38 by activating ERK1/2, promoting astrocyte mitochondrial transfer.
The Sigma-2 receptor (σ2R), which has no structural similarity with the sigma-1 protein, is a 176 amino acid-long, 21 kDa, is an integral endoplasmic reticular membrane chaperone protein, coded by the gene TMEM97/SIGMAR2 on chromosome 17q11, and widely expressed in the central nervous system in the liver and in the kidney, involved in cellular cholesterol homeostasis, lipid metabolism, proteolytic degradation of non-productive precursors, and is critical for the removal of mitochondrial precursor proteins on the ER surface, influencing sterol homeostasis. Sigma2 Receptor and Progesterone Receptor Membrane Component 1 (PGRMC1) forms a ternary complex with the Low-Density Lipoprotein Receptor, as well as cholesterol transport out of lysosome by interacting with Niemann–Pick C1 protein (NPC1), which is chaperonized by Sigma-2, and this intact complex is required for efficient uptake of lipoproteins such as LDL and apolipoprotein E (apoE). These receptors are expressed in the nervous system where they have implications in neurodegenerative diseases such as Alzheimer’s Disease, where apoE is involved in neuronal uptake and accumulation of Aβ42. Specific endogenous ligands of Sigma2-receptor are 20(S)-OHC and Histatin-1 (Hst1), with important roles in cell migration and immune response.