Compound | Target/mechanism of action | Clinical trial status in WS | References |
---|---|---|---|
4-Phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) | Chemical chaperones: stabilize protein conformation during folding, ameliorate trafficking of mutant proteins, suppress unfolded protein aggregation | Â | [71] |
Dantrolene | Blocks ryanodine receptor in the ER membrane: stabilize ER calcium level by suppressing the efflux of calcium from ER to cytosol | Clinical trial of dantrolene sodium in pediatric and adult patients with WS, ClinicalTrials.gov: NCT02829268 | |
Pioglitazone | Inhibits inositol triphosphate (IP3R)-mediated release of calcium from the ER | Â | |
Rapamycin | Reduces cytoplasmic calcium by a mechanism similar to pioglitazone | Â | [76] |
Carbachol | Muscarinic receptor 3 (M3) agonist: mobilizes intracellular calcium stores and potentiates glucose-stimulated insulin secretion | Â | |
Liraglutide, exenatide, semaglutide | Glucagon-like peptide-1 receptor (GLP-1R) agonists. They activate PERK-ATF4 pathway and interfere with the ER unfolded protein response | Â | |
Sitagliptin, vildagliptin, gemigliptin | Inhibitors of dipeptidyl peptidase-4 (DPP-4), an enzyme that deactivates GLP-1, thus also increasing GLP-1 levels | Â | [71] |
Salubrinal | Selective inhibitor of the eIF2α phosphatase |  | |
Valproate acid (VPA) | Promotes the expression of both WFS1 and ER chaperones and attenuates ER-induced apoptosis | Efficacy and safety trial of sodium valproate in pediatric and adult patients with WS, ClinicalTrials.gov: NCT03717909 |