Early Stage Discovery and Validation of Pharmacological Chaperones for the Correction of Protein Misfolding Diseases
Pharmacological chaperones are small molecular weight molecules that bind specifically to protein targets and stabilize unstable and misfolded conformations. In particular, there is an increasing interest in the application of this type of compounds for the correction of genetic conformational disorders, which are caused by mutations leading to protein instability. The discovery of compounds with pharmacological chaperone ability is customarily initiated by a high-throughput screening of chemical libraries searching for stabilizing binders. However, there is no established consensus for the subsequent steps. Therefore, here, we introduce an example of a successful protocol directed to the discovery of pharmacological chaperones with potential for the therapeutic correction of phenylketonuria, a defect caused by mutations in the enzyme phenylalanine hydroxylase.
KeywordsDrug discovery and development Orthogonal binding assays Functional assays
This work was supported by The Research Council of Norway (RCN; Program Forny2020 248889/O30 and FRIMEDBIO 214012), the infrastructure project Nor-Openscreen (RCN), and The K.G. Jebsen Foundation. We thank Guri E. Matre and Ming Ying for expert technical assistance.
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