Researchers identified 2 furan derivatives that inhibited the aquaporin-1 (AQP1) cation conductance, modified hemoglobin, and effectively prevented cell sickling in sickle cell disease (SCD), as published in Frontiers in Pharmacology.

“Novel therapeutic agents with combined actions on AQP1 ion channel inhibition and [hemoglobin carrying the SCD mutation] stabilization could offer the desired slowing of dehydration and [hemoglobin carrying the SCD mutation] polymerization, a goal of international interest for expanding the range of affordable clinical options for treating sickle cell disease,” the researchers said.

Among the 4 compounds tested, 5-(phenoxymethyl)furan-2-carbaldehyde (5-PMFC) was the most potent inhibitor of the cationic conductance of AQP1 and the most effective in reducing cell sickling. No AQP1 reactivation was observed after 2 h incubation with 0.5 mM 5-PMFC.

Tert-butyl (5-formylfuran-2-yl)methyl carbonate also caused moderate inhibition of AQP1 cation conductance. It scored second in the magnitude of sickle cell inhibition at 2 mM, following 5-PMFC.

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In contrast, 5-(2-nitrophenoxymethyl)-furan-2-carbaldehyde (5-NMFC) and 5-(4-chlorophenoxymethyl)furan-2-carbaldehyde did not block AQP1 cation conductance at concentrations up to 2 mM. Although these 2 compounds were able to modify hemoglobin, they were less effective in reducing cell sickling.

To better understand if hemoglobin carrying the SCD mutation modification added value to AQP1 inhibition as a therapeutic approach, the researchers cotreated human SCD red blood cells with the bumetanide derivative AqB011 (a pharmacological inhibitor of the AQP1 ion conductance) and the 5-NMFC compound, which modified hemoglobin without blocking AQP1. The combined treatment enhanced the protection of human SCD red blood cells from sickling during hypoxia.

“Candidate drugs, perhaps similar to 5-PMFC with combined actions on both hemoglobin carrying the SCD mutation stabilization and AQP1 ion channel inhibition, could be valuable starting points for generating affordable clinical options for treating sickle cell disease around the world,” the authors concluded.

Reference

Chow PH, Cox CD, Pei J V, et al. Inhibition of the aquaporin-1 cation conductance by selected furan compounds reduces red blood cell sickling. Front Pharmacol. 2022;12. doi:10.3389/fphar.2021.794791