Second-Generation Pharmacological Chaperones: Beyond Inhibitors

Abstract

<jats:p>Protein misfolding induced by missense mutations is the source of hundreds of conformational diseases. The cell quality control may eliminate nascent misfolded proteins, such as enzymes, and a pathological loss-of-function may result from their early degradation. Since the proof of concept in the 2000s, the bioinspired pharmacological chaperone therapy became a relevant low-molecular-weight compound strategy against conformational diseases. The first-generation pharmacological chaperones were competitive inhibitors of mutant enzymes. Counterintuitively, in binding to the active site, these inhibitors stabilize the proper folding of the mutated protein and partially rescue its cellular function. The main limitation of the first-generation pharmacological chaperones lies in the balance between enzyme activity enhancement and inhibition. Recent research efforts were directed towards the development of promising second-generation pharmacological chaperones. These non-inhibitory ligands, targeting previously unknown binding pockets, limit the risk of adverse enzymatic inhibition. Their pharmacophore identification is however challenging and likely requires a massive screening-based approach. This review focuses on second-generation chaperones designed to restore the cellular activity of misfolded enzymes. It intends to highlight, for a selected set of rare inherited metabolic disorders, the strategies implemented to identify and develop these pharmacologically relevant small organic molecules as potential drug candidates.</jats:p>

Mechanism of CFTR correction by type I folding correctors

“…This concept, rooted in the energetics of protein folding, may also apply to other pharmacological chaperones targeting various misfolded proteins. As of today, most small molecule chaperones were developed as competitive inhibitors binding at the enzymatic active sites (Tran et al, 2020). The disadvantage of this approach is that the drug stabilizes folding of the disease-causing mutants but at the same time it diminishes enzymatic activity.…”

Protein structural features predict responsiveness to pharmacological chaperone treatment for three lysosomal storage disorders

“…A smaller amount of the protein is then available to carry out its function, particularly since the destabilized protein is more likely to be cleared by quality control machinery (6)(7)(8). One potential treatment for diseases caused by destabilized variants is a small molecule drug that helps stabilize the mutant protein, called a pharmacological chaperone (9)(10)(11)(12).…”

Iminosugar C‐Glycosides Work as Pharmacological Chaperones of NAGLU, a Glycosidase Involved in MPS IIIB Rare Disease**

“…We therefore tentatively hypothesize that β‐HNJNAc also exert a non‐inhibitory pharmacological chaperone effect on E153K mutated NAGLU, a mutation expected to disrupt the overall fold of the protein [16] . Such allosteric ligands, including L‐iminosugars, [27c,29] have been already identified for several LSDs [30] including Fabry, [31] Pompe [32] and Krabbe [33] diseases. They act by targeting previously unknown binding pockets, thus limiting the risk of adverse enzymatic inhibition.…”