Water impermeable membrane
Biological cells are water filled compartments that are engulfed by greasy, water repelling, lipid membranes, which restrict the movement of water and dissolved substances between cells. This compartmentalization was likely an essential step for the beginning of life on earth, since it allows keeping reactants for chemical processes in place.
The existence of water channels was a matter of scientific debate until the discovery of aquaporin-1 in 1991, which resulted in the 2003 Nobel Prize in Chemistry to Professor Peter Agre. Aquaporin-1 was later found to be highly abundant in kidneys, where is allows the filtration process that eliminates metabolic waste products from the blood and concentrates 180 litres of primary filtrate to just 1-2 litres of daily excreted urine. Similar proteins of the aquaporin family were also found in tiny bacteria and facilitate water movement from roots to leaves in giant Sequoia trees.
After the initial discovery of aquaporins as water (chemical formula: H2O) channels, it has become clear more recently that the same proteins can often also facilitate movement of the similar chemical hydrogen peroxide (chemical formula: H2O2) across cell membranes.
Importantly, hydrogen peroxide acts as a messenger, conferring chemical signals between cells from the outside of the lipid membrane to the inside. Such signals can lead to the coordinated gathering of immune cells at sites of infection, or to enhanced phagocytosis.
Aquaporin-9 mediates cytokine signals
Aquaporin-9 mediated water and hydrogen peroxide transport is required for efficient migration of immune cells to infections sites, and for their messaging for re-enforcement. Blocking of the aquaporin-9 channel can thus help to restore the balance between pro-inflammatory and anti-inflammatory immune cells.
After the initial discovery of aquaporins as water (chemical formula: H2O) channels, it has become clear more recently that the same proteins can often also facilitate movement of the similar chemical hydrogen peroxide (chemical formula: H2O2) across cell membranes. Importantly, hydrogen peroxide acts as a messenger, conferring chemical signals between cells from the outside of the lipid membrane to the inside. Such signals can lead to the coordinated gathering of immune cells at sites of infection, or to enhanced phagocytosis.
Balancing the immune response
Furthermore, such signals can lead to the activation of immunologic weapons that kill bacteria and viruses. Some of these weapons, such as antibodies are very specific to the respective invader. However, most early response weapons to invaders are crude and need to be tightly controlled, or nearby tissues and organs can be harmed. Control of the immune system is established in a finely balanced chemical communication between pro-inflammatory (attacking) and anti-inflammatory (soothing) immune cells.
In a number of human diseases the immune system loses balance. In sepsis (blood-poisoning), pro-inflammatory immune cells gather at infection sites, and once there call for re-enforcement. Even if the invading bacteria or viruses are killed in the process, the harsh immune reaction can lead to long-lasting tissue damage, and in many cases is even fatal.
The potential value of aquaporin blockers as novel therapeutics in sepsis, but also in many other diseases e.g. diabetes and cancer has long been recognized. However, the identification of drug-like chemicals that can inhibit aquaporins by blocking the channel pore was unsuccessful for many years.
It was an innovative collaboration between molecular biologists at Aarhus University in Denmark, structural and computational biologists at Lund University in Sweden, and Chemists at Red Glead Discovery in Lund that was finally able to provide a solution for this problem, and identified suitable aquaporin-9 inhibitors.
This team of experts and the resulting intellectual property has now been integrated in ApoGlyx. In an exciting in vivo study, conducted at the renowned William Harvey Research Institute in London, UK, a prototype aquaporin-9 inhibitor has recently been found to provide a profound protection from sepsis induced organ damage in an in vivo disease model.
It is our ambition in ApoGlyx to translate this finding into a therapy that can save lives and moreover, improve the quality of life for sepsis survivors in the future.
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- Sonntag, Y., P. Gena, A. Maggio, T. Singh, I. Artner, M.K. Oklinski, U. Johanson, P. Kjellbom, J.D. Nieland, S. Nielsen, G. Calamita, and M. Rutzler, Identification and characterization of potent and selective aquaporin-3 and aquaporin-7 inhibitors. J Biol Chem, 2019. 294(18): p. 7377-7387. http://www.ncbi.nlm.nih.gov/pubmed/30862673.
- Rudd, K. E., S. C. Johnson, et al. (2020). "Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study." Lancet 395(10219): 200-211.
- Verkman, A. S., M. O. Anderson, et al. (2014). "Aquaporins: important but elusive drug targets." Nat Rev Drug Discov 13(4): 259-277.
- Wacker, S. J., C. Aponte-Santamaria, et al. (2013). "The identification of novel, high affinity AQP9 inhibitors in an intracellular binding site." Mol Membr Biol 30(3): 246-260.
- Zhou, F., T. Yu, et al. (2020). "Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study." Lancet 395(10229): 1054-1062.
Zhou, F., T. Yu, et al. (2020). "Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study." Lancet 395(10229): 1054-1062.
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