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Thormann M
,
Traube N
,
Yehia N
,
Koestler R
,
Galabova G
,
MacAulay N
,
Toft-Bertelsen TL
.
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Cerebral edema is a life-threatening condition that can cause permanent brain damage or death if left untreated. Existing therapies aim at mitigating the associated elevated intracranial pressure, yet they primarily alleviate pressure rather than prevent edema formation. Prophylactic anti-edema therapy necessitates novel drugs targeting edema formation. Aquaporin 4 (AQP4), an abundantly expressed water pore in mammalian glia and ependymal cells, has been proposed to be involved in cerebral edema formation. A series of novel compounds have been tested for their potential inhibitory effects on AQP4. However, selectivity, toxicity, functional inhibition, sustained therapeutic concentration, and delivery into the central nervous system are major challenges. Employing extensive density-functional theory (DFT) calculations, we identified a previously unreported thermodynamically stable tautomer of the recently identified AQP4-specific inhibitor TGN-020 (2-(nicotinamide)-1,3,4-thiadiazol). This novel form, featuring a distinct hydrogen-bonding pattern, served as a template for a COSMOsim-3D-based virtual screen of proprietary compounds from Origenis™. The screening identified ORI-TRN-002, an electronic homologue of TGN-020, demonstrating high solubility and low protein binding. Evaluating ORI-TRN-002 on AQP4-expressing Xenopus laevis oocytes using a high-resolution volume recording system revealed an IC50 of 2.9 ± 0.6 µM, establishing it as a novel AQP4 inhibitor. ORI-TRN-002 exhibits superior solubility and overcomes free fraction limitations compared to other reported AQP4 inhibitors, suggesting its potential as a promising anti-edema therapy for treating cerebral edema in the future.
Figure 1. Identification of an electronic homologue of TGN-020. Commonly used chemical structure of TGN-020 (A). Three tautomers of TGN-020 (B). Unit cell of TGN-020 X-ray structure (C). TGN-020 X-ray structure (D). COSMO-RS surface of the most stable conformer of TGN-020 (B(iii)), displaying shape and hydrogen-bonding pattern (red, HB acceptor; blue, HB donor) (E). Chemical structure of ORI-TRN-002 (F). COSMO-RS surface of ORI-TRN-002, displaying shape and hydrogen-bonding pattern (red, HB acceptor; blue, HB donor), aligned with (E,G).
Figure 2. ORI-TRN-002 displays drug-like properties. The chemical structures of the three AQP4 inhibitors studied and their measured physico-chemical properties (logD at pH 7.4, log10 of molar human serum albumin affinity constant, percent human plasma protein binding, log10 of human alpha acid glycoprotein affinity constant, unbound fraction in liver, and unbound fraction in hepatocytes)
Figure 3. ORI-TRN-002-mediated inhibition of AQP4. Volume traces from an AQP4-expressing oocyte and an uninjected oocyte challenged with a hyposmotic gradient (indicated by a blue bar) (A inset). Summarized water permeabilities from uninjected—or AQP4-expressing—oocytes (n = 11) (A). Volume traces from an untreated AQP4-expressing oocyte or AQP4-expressing oocytes treated with ORI-TRN-002 (ORI), AER-270, or TGN-020 and challenged with a hyposmotic gradient (indicated by a blue bar) (B inset). Summarized water permeabilities from oocytes expressing AQP4, either untreated or pretreated with ORI-TRN-002 (ORI), AER-270, or TGN-020 for 60 min (n = 11) (B). Membrane potential monitored from the AQP4-expressing oocytes in control solution or after 60 min of pretreatment with ORI-TRN-002 (ORI) (C) ANOVA followed by Tukey’s multiple comparison tests or Student’s t-test were used as statistical test. *** p < 0.001.
Figure 4. ORI-TRN-002 exerts an acute blocking effect on AQP4. A representative time-control experiment from an AQP4-expressing oocyte and volume traces from AQP4-expressing oocytes treated with ORI-TRN-002 (ORI), AER-270, or TGN-020 repeatedly challenged with a hyposmotic gradient (indicated by a blue bar, t = 0 min (control), t = 10 min) (A inset). Summarized water permeabilities at t = 0 min (control) and t = 10 min from oocytes expressing AQP4, either untreated or treated with ORI-TRN-002 (ORI), AER-270, or TGN-020 (n = 9) (A). Membrane potential monitored from the AQP4-expressing oocytes in control solution or upon treatment with ORI-TRN-002 (ORI) (B). AQP4-expressing oocytes exposed to different concentrations of ORI-TRN-002 (or vehicle (DMSO) only; ‘Control’). Data were fitted with Graphpad Prism using nonlinear regression analysis to obtain the IC50 from the mean of the independent regression analyses (n = 6) (C). ANOVA followed by Tukey’s multiple comparison tests were used as statistical test. *** p < 0.001.
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