Chemical chaperones have been shown to be able to prevent protein aggregation. However, using chemical chaperones as drugs against the diseases which are related to the protein aggregation is limited by their very high active concentrations (mM range) required for the effect. One of the most common chemical chaperones is 4-phenylbutyric acid (4-PBA). Despite, its non-favorable pharmacokinetic properties, 4-PBA was approved as a drug to treat ornithine cycle diseases. We discovered that, 2-isopropyl-4-phenylbutanoic acid (2I4PBA) is more potent (2-10-fold) and more effective than 4-PBA in several general protein aggregation in vitro models. Importantly, it reduced the secretion rate of autism-linked Arg451Cys Neuroligin3 (R451C NLGN3), most likely favoring its degradation by an indirect mechanism. Also, the direct chaperoning effect of 2I4PBA was studied and we showed that the compound is more active and potent compering to the parent molecule: 4-PBA.

We also are developing several chemical chaperones in which PBA and lipoic acid were conjugated with lysosome, ER targeted moieties or with lipophilic membrane penetrating moieties. Some of them exhibited a significant biological effect in the mutated SOD1 and C9orf72 dipeptide repeat in experiments in vitro and in ALS Drosophila models.