GSNO Therapeutics, Inc

Science of Protein Nitrosylation and GSNOR Inhibition

GSNOR Inhibitors: Novel MOA

GSNO Details

Novelty and MOA of GSNO Therapeutics’ GTI-850

GSNOR Inhibition Is a Single Drug Target that Results in a Multi-mechanism Therapy for Inflammatory, Oxidant-Based, Mitochondrial, and Fibrotic Diseases

As Charles Darwin published “On the Origin of Species” more than 150 years ago, evolution through natural selection has produced the amazing phenotypic diversity of living organisms on Earth. Evolution has also shaped the molecular and cellular systems that regulate the physiology of all those species. Some systems are very different—photosynthesis in plants, which is absent in animals. However, other systems, mainly signaling systems, are very similar between species. One prominent example is the protein S-nitrosylation signaling system which has been in evolution for 2-3 billion years and is important in the multi-competent cells in the hemolymph of an arthropod—the American horseshoe crab—is one prominent example (Limulus polyphemus), an animal which has changed little over 500 million years of evolution [1] and still depends upon its nitrosylation pathways. All other eukaryotes alive today depend on this system for a diverse set of physiological responses, many of which can cause disease when misregulated.
DNA Illustration
The importance of protein S-nitrosylation in physiology and medicine was discovered in 1977 when nitric oxide (NO), a gas, was discovered to have important signaling roles in many different cells and organs. That discovery resulted in the awarding of Nobel Prizes in 1998 to Ferid Murad, Robert F. Furchgott, and Louis J. Ignarro. Dr. Murad joined the scientific advisory board of GSNO Therapeutics in December 2016, and he both supports and plays a key role in our programs.
Given the fact that nitrosylation, as a physiological regulator, has been conserved in evolution for so long implies that it must play a crucial role in maintaining organismal homeostasis, or it would have been eliminated by evolution if it produced toxic consequences. Those roles are expected to be significant and diverse because evolution tends to reutilize a signaling pathway for multiple applications. In fact, when all protein S-nitrosylation from nitric oxide and GSNO were eliminated in your body, you would die within seconds. GSNO Therapeutics, based on its data and surveys of the relevant literature, believes that sufficient data exists to prove that nitrosylation plays major pleiotropic roles in regulating multiple important therapeutic pathways. To date, those expectations have been realized.

As support for these hypotheses, GSNO Therapeutics and its collaborators have demonstrated that inhibiting the enzyme S-nitrosoglutathione reductase (GSNOR) increases the levels of S-nitrosylation on critical proteins and produces numerous therapeutic benefits that are relevant to many important diseases across multiple organ systems. GSNOR is a reductase that breaks down or reduces S-nitrosoglutathione (GSNO), which is the stable, cellular storage form of S-nitrosylating activity, performing 90% of all cellular nitrosylation. GSNO has a half-life of 5.5 hours in the body and does not break down to NO, but, like NO, nitrosylates cysteines on evolutionarily selected signals and other proteins. NO, in contrast, is extremely reactive with a tissue half-life of seconds and limited tissue penetration, whereas GSNO’s longer half-life and extensive cellular and plasma distribution make it the carrier of the major S-nitrosylating activities. NO reacts as an SN1 type reaction, whereas GSNO uses a different SN2 type of chemical reaction. Both compounds S-nitrosylate solvent accessible cysteines on evolutionarily selected proteins, thereby changing the structure and function of those proteins. Thus, GSNO is the “real API” of precision-targeted GSNORIs.

Thus, by inhibiting the breakdown of GSNO by inhibiting GSNOR, the cellular levels of GSNO increase, which trans-nitrosylates by an SN2 type reaction critical proteins that activate evolutionarily selected therapeutic pathways, GSNO Thera’s small molecule platform regulates cellular nitrosylation, which provides, so far, 56 identified therapeutic benefits for multiple diseases with complex pathophysiological drivers, and all without any safety issues identified. Safely regulating so many disease drivers should be more successful at benefitting complex diseases than regulating only one or a few drivers. To date, 26 animal disease models and two human diseases have been therapeutically benefited by GSNORi technology.

GSNO itself is a natural metabolite that has been shown to be non-toxic in animal studies and is freely bioavailable in blood and body tissues, and can move from the intestine or other tissues into many organs, including hard-to-access brain ocular spaces. Thus, GSNO is the “real” Active Pharmaceutical Ingredient (API) of GSNORi technology that does the actual therapeutic work by nitrosylating under-nitrosylated proteins in signal pathways to effect therapy. GTI-850 does not directly affect any of the MOAs that it produces. Rather, GSNO does that.

Many human diseases and animal models have increased GSNOR, which can be normalized by inhibiting GSNOR. But, GSNORi is still active even without GSNOR overexpression. Like phosphorylation, nitrosylation is a post-translational protein regulatory system, but one regulated by only one enzyme, GSNOR, rather than by 700+ as with phosphorylation. Therefore, nitrosylation regulation by GSNORi is a much more druggable technology than phosphorylation regulation by so many often overlapping kinase and phosphatase targets, many of which produce toxicity, which GSNORi does not.

Our lead molecule, GTI-850, is a composition of matter compound that we invented and own all rights to. It has no toxicity in sub-chronic safety studies or in vitro studies against 44 common targets of toxicity. GTI-850 has an unusual PK/PD relationship. It has only 0.2% oral bioavailability, yet 20-40% oral bioactivity compared to its IV bioactivity. Why? The answer is that oral GTI-850, while not systemically distributed, inhibits GSNOR in the intestine, which raises GSNO concentrations there, and GSNO moves into the blood and circulates throughout the body and into many organs, including the brain and other neural tissues, where it nitrosylates undernitrosylated proteins for therapeutic benefits.
The intestine expresses high concentrations of GSNOR over its entire surface area, which is huge and communicates directly with the blood circulation. The lack of systemic circulation of GTI-850, along with potent bioactivity, greatly increases the probability of clinical success because none of the typical hazards apply that cause drugs to fail in safety or produce a low therapeutic risk/benefit equation for even marketed drugs. Because GTI-850 remains in the intestine, it will not have the following typical systemic safety issues: no first-pass metabolism, no toxic metabolites, no drug-drug interactions, no inhibition of liver CypP450s, no inadequate PK, no tissue accumulation, and no off-target toxicity. The drug is active with a single dose for acute diseases and at once-a-day dosing in chronic animal disease models.

The 56 therapeutic disease benefits of GSNORis include the inhibition of oxidative stress, nitrosative stress, cytokines, chemokines, and inflammatory cells, including microglia, TNF-, TGF-β, ICAM-1, VCAM-1, NfKB, STAT3, iNOS, IL-1β, NLRP3 inflammasomes, Calcium dysregulation, Mitochondrial dysregulation, NOX-4, Endoplasmic reticulum stress, Vascular dysfunction/hypoperfusion, Blood pressure in hypertensive, but not normotensive rats, Brain amyloid β, Brain Tau hyper-phosphorylation, iNOS over-expression, Nitrotyrosine expression in brain, Brain GSK 3 β and Cdk5 pathways, Brain calpain/p25/Cdk5 pathways, Hyperglycemia, Plasma glucose, Steatosis, Fibrosis, Pain, Misfolded proteins, MMP-9, BBB breakdown, and Platelet aggregation. Activation of IL-4, IL-10, Neurotrophic factor BDNF, Neurotrophic factor CNTF, Neurotrophic factor Synaptophysin, Neurotrophic factor TrkB/pTrkB, Memory and learning, Neurological function, sGC/cGMP, Nrf-2 antioxidant system for ROS & RNS, and Mitochondrial prohibitin for preventing/reversing mitochondrial dysfunction. Most therapies available today and in development target only one of those drivers. Which do you think will be more effective? Please see below for the complete list.
Given this wide range of therapeutic activity, and the demonstrated activity in 26 disease models and counting, there are many clinical development options GSNO Thera can choose from. Our preference is to go for the disease(s) with the most unmet medical needs and the largest patient populations. Neurodegenerative and ophthalmic/ocular diseases are obvious choices. The 26 disease models in which GSNORis are active include ocular diseases, such as acute ocular inflammation and retinal degeneration, inflammatory and autoimmune diseases, such as rheumatoid and osteoarthritis, Crohn’s disease, ulcerative colitis, and psoriasis, etc., metabolic diseases, such as diabetes and non-alcoholic steatohepatitis, cardiovascular diseases, such as acute heart attack and heart failure, respiratory diseases, such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and asthma, renal diseases, such as high salt-induced chronic kidney disease and vascular dysfunction, neurodegenerative diseases, such as traumatic brain injury and multiple sclerosis, predicted Alzheimer’s and Parkinson’s disease based on the inhibition of oxidant damage, inflammation, amyloid β, Brain Tau hyper-phosphorylation, and 56 total disease drivers (see above).
  1. Anti-inflammation: Reduction in the number of eosinophils and lymphocytes that infiltrate inflamed tissue; inhibition of ICAM-1; inhibition of the cytokines: IFN-y, TNF-a, TGF-ß, IL-4, IL-5, IL-6, IL-12(p40), IL-12(p70), IL-13, Il-17, and IL-23 [References 2, 3, 4, and GSNO Thera unpublished].
  2. NFkB: Inhibition of the activation of NF?B by increasing the S-nitrosylation of I??ß, which inhibits its kinase activity and suppresses NF?B activation [5] and, in turn, decreases the expression of inflammatory genes.
  3. Inhibition of the chemokines CCL-2 (MCP-1) and CCL11: CCL-2 recruit monocytes, memory T cells, and dendritic cells to the sites of inflammation produced by either tissue injury or infection. CCL-11 selectively recruits eosinophils by inducing their chemotaxis and, therefore, is implicated in allergic responses. Both are involved in inducing fibrosis in various tissues [2,3].
  4. Antioxidant: Induction of Nrf2/ARE system of antioxidant enzymes to inhibit the production of reactive oxygen species (ROS) [6], which are causative in the induction of fibrosis [7,8].
  5. Anti-fibrotic: GTI-334 (formerly SPL-334) prevents the progression of fibrosis and reverses existing bleomycin-induced fibrosis [3] due to inhibition of ROS, CCL-2, CCL-11, and Connective tissue Growth Factor (CTGF). Reversal of existing fibrosis is almost unprecedented among clinical candidates. GTI-850 prevents NASH in both a male and a female mouse model of the disease.
  6. EMT: Attenuation of epithelial-mesenchymal transition (EMT) as measured by decreased TGF-ß induced collagen synthesis in human fibroblast cells in vitro [3].
  7. Bronchodilation through the opening of constricted bronchioles [2,4].
  8. Increased mucus clearance [2].
  9. Activation of Soluble Guanylyl Cyclase (sGC), which regulates the cyclic guanosine monophosphate (cGMP) system [5]. cGMP acts as a second messenger, much like cyclic AMP. Its mechanism of action is the activation of intracellular protein kinases in response to the binding of membrane-impermeable peptide hormones to the external cell surface.

GSNOR inhibition increases the nitrosylation of evolutionarily selected signal transduction proteins by increasing the cellular concentration of S-nitrosoglutathione (GSNO), which trans-nitrosylates accessible regulatory cysteines. Trans-nitrosylation by GSNO proceeds by a different chemical mechanism than nitrosylation by NO. GSNO does not produce. NO, as some literature suggests. Furthermore, GSNOR inhibition does not cause nitrosative stress but rather prevents it [6,9,10]. This lack of nitrosative stress is a clear advantage for using GSNOR inhibition rather than exogenous NO itself or non-specific NO donors to affect the therapeutic benefits of nitrosylation.

By inhibiting GSNOR, we simultaneously activate many signal pathways in a natural and balanced way to promote multi-faceted therapeutic outcomes, as noted above. This balanced approach is in contrast to drugs that inhibit or inactivate a single target that is disease-related—TNF-α, TGF-β, IL-6, and many others. The evidence shows that our GSNOR inhibition approach is more efficacious and safer because we are simultaneously regulating many disease processes in a balanced way, not obliterating a single disease driver that may also have other important physiological roles. While single effect drugs, such as MABs, have therapeutic efficacy, we believe that our multi-effect drugs will be both safer and more effective for many diseases with multiple and complex pathophysiological drivers—those of primary medical need today.

Some ask: How can one drug have so many therapeutic activities? The answer is that GSNOR controls ~90% of cellular nitrosylation, which, like phosphorylation, is a post-translational modification that regulates many critical signal pathways, including those above. However, phosphorylation is regulated by 500+ kinases and 200+ phosphatases. Thus, phosphorylation is much less druggable than nitrosylation, which is regulated primarily by GSNOR and GSNO.
In summary: We believe GSNO Therapeutics and the literature’s data suggest that GSNOR inhibition represents a new paradigm in the pharmacological therapy of many human and animal diseases. The multiple effects that result from inhibiting GSNOR are able to simultaneously regulate multiple disease pathways in a controlled, evolutionarily selected way that avoids toxicity. Thus, GSNOR inhibition by small molecules provides powerful synergistic therapies for many important diseases, with so far no identified toxicity in preclinical and 400-patient clinical trials.

References for All of the Data Discussed Above

  1. Anderson, C.J., Kahl A., Qian L., Stepanova, A., Starkov A., Manfredi G., Iadecola C., & Zhou P. (2018 Aug). Prohibitin is a positive modulator of mitochondrial function in PC12 cells under oxidative stress. J Neurochem. 146(3):235-250. DOI: 10.1111/jnc.14472.
  2. Annamalai, B., Won, JS, Choi, S., Singh, I., & Singh, AK. (2015 Feb). Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation. Biochem Biophys Res Commun. 2015 Feb 27;458(1):214-9. DOI: 10.1016/j.bbrc.2015.01.093. Epub 2015 Jan 29. PMID:25640839.
  3. Artaud-Macari, E., Goven, D., Brayer, S., Hamimi, A., Besnard, V., Marchal-Somme, J., Al,i ZE., Crestan,i B., Kerdine-Romer, S., Boutten, A., and Bonay, M. (2013). Nuclear factor erythroid 2-related factor 2 nuclear translocation induces myofibroblastic dedifferentiation in idiopathic pulmonary fibrosis. Antioxidants & redox signaling 18:66-79.
  4. Assreuy, J., et al., Feedback inhibition of nitric oxide synthase activity by nitric oxide. Br J Pharmacol, 1993. 108(3): p. 833-7.
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  7. Chen, Qiumei, Richard E. Sievers, Monika Varga, Sourabh Kharait, Daniel J. Haddad, Aaron K. Patton, Christopher S. Delany, Sarah C. Mutka, Joan P. Blonder, Gregory P. Dubé, Gary J. Rosenthal, and Matthew L. Springer. Pharmacological inhibition of S-nitrosoglutathione reductase improves endothelial vasodilatory function in rats in vivo. Appl Physiol 114: 752–760, 2013.
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