Publications

The following publications provide more information about SAJE’s technology.

While many of these publications use SPL-334, our first GSNOR inhibitor, our novel lead compound, SPL-850, inhibits the same disease drivers, except that it is a superior GSNOR inhibitor against the enzyme in vitro and in vivo and is a composition of matter compound, whereas SPL-334 has only limited use protection.

Heart Attack and Neuroprotection: This publication provides evidence for the potent activity of our first generation GSNORi, SPL-334.1, in increasing survival after heart attack (from 35% survival in disease control mice to 82% in SPL-334.1 –treated animals) and decreasing the devastating neurological damage (from 22% of normal in disease control animals to 91% in SPL-334.1-treated animals). The work is the result of an ongoing collaboration between SAJE and the Ichinose laboratory at Harvard’s MGH. Although not yet published, we have also demonstrated potent activity of SPL-891.1 against heart failure and stroke. SPL-850 and 891.1 are superior GSNOR inhibitors compared to SPL-334.1, our first generation inhibitor. Kei Hayashida, Aranya Bagchi, Yusuke Miyazaki, Shuichi Hirai, Divya Seth, Michael G. Silverman, Emanuele Rezoagli, Eizo Marutani, Naohiro Mori, Aurora Magliocca, Xiaowen Liu, Lorenzo Berra, Allyson G. Hindle, Michael W. Donnino, Rajeev Malhotra, Matthews O. Bradley, Jonathan S. Stamler, Fumito Ichinose. Improvement in Outcomes After Cardiac Arrest and Resuscitation by Inhibition of S-Nitrosoglutathione Reductase. Circulation, 2019; 139: 815-827.

In vitro Data for a First GSNORi: This paper details some of the key in vitro and organ culture data that illustrates the activity of its first generation GSNOR inhibitor, SPL-334. It shows that GSNOR inhibition causes increases in cellular proteins, including those involved in inflammation, and that it induces the sGC/cGMP axis. Sanghani, P. C., Davis, W. I., Fears, S. L., Green, S. L., Zhai, L., Tang, Y., Martin, E., Bryan, N. S., and Sanghani, S. P. (2009) Kinetic and cellular characterization of novel inhibitors of S-nitrosoglutathione reductase, J Biol Chem 284, 24354-24362. Published online 2009 Jul 11. doi: 10.1074/jbc.M109.019919.

Asthma: This work demonstrates that SPL-334 is highly active in an inhalation model of asthma and some of the cytokine, chemokine, and inflammatory cell drivers of asthma. It was a collaboration between SAJE and the Roberts/Jaffar lab at the University of Montana: Ferrini, M. E., Simons, B. J., Bassett, D. J., Bradley, M. O., Roberts, K., and Jaffar, Z. (2013) S-nitrosoglutathione reductase inhibition regulates allergen-induced lung inflammation and airway hyperreactivity, PLoS One. 2013 Jul 25;8(7):e70351. doi: 10.1371/journal.pone.0070351. Print 2013.

Idiopathic Pulmonary Fibrosis (IPF): This publication shows that SPL-334 is highly active in a bleomycin mouse model of IPF, and reverses fibrosis. It is a collaboration between SAJE and the Atamas/Luzina lab at the University of Maryland School of Medicine, using SPL-334 in a gold-standard model of IPF. Pharmacological in vivo inhibition of S-nitrosoglutathione reductase attenuates bleomycin-induced inflammation and fibrosis. Irina G. Luzina, Virginia Lockatell, Nevins W. Todd, Pavel Kopach, Helen Pentikis, Sergei P. Atamas. Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201 (I.G.L., V.L., N.W.T., P.K., S.P.A); SAJE Pharma, Baltimore, MD 21218 (H.P.). JPET Fast Forward. Published on July 24, 2015 as DOI: 10.1124/jpet.115.224675

Asthma: This abstract was published by scientists at Duke University, with whom we have a collaboration. GSNORi in their abstract is the same compound as SPL-334: Systemic And/Or Local Aerosol Inhibition Of S-Nitrosoglutathione Reductase (GSNOR) Ameliorates Physiologic, Biologic, And Proteomic Phenotypes In An Allergic Mouse Model Of Inflammatory Airway Disease. Loretta G. Que, Matthew W. Foster, Erin N. Potts, Erik J. Soderblom, Zhonghui Yang, David M. Gooden, M. A. Moseley, and W M. Foster. Chapter DOI: 10.1164/ajrccm-conference.2011.183.1_MeetingAbstracts.A407510.

Nrf-2 Induction: This paper was also done by the Duke scientists and shows that SPL-334 (referred to as GSNORi in their paper) induces Nrf2, the anti-oxidant response element transcription factor: Foster, M. W., Yang, Z., Gooden, D. M., Thompson, J. W., Ball, C. H., Turner, M. E., Hou, Y., Pi, J., Moseley, M. A., and Que, L. G. (2012) Proteomic characterization of the cellular response to nitrosative stress mediated by s-nitrosoglutathione reductase inhibition, J Proteome Res 11, 2480-2491.

Nrf-2 Induction: This abstract was published by scientists at GSK and corroborates the work by Duke showing that SPL-334(referred to as GSNORi in the GSK abstract) induces Nrf2. Inhibition of S-Nitroso Glutathione Reductase (GSNOR) Up-Regulates The Nrf2 Pathway In Human Bronchial Epithelial Cells. Diana G. Chalupowicz and Yolanda Sanchez Lopez-Boado. http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2013.187.1_MeetingAbstracts.A1837