Suppression of toxicity of the mutant huntingtin protein by its interacting compound, desonide

Abstract

Significance Classical drug discovery identifies inhibitors that block the activities of pathogenic proteins. This typically relies on a measurable biochemical readout and accessible binding sites whose occupancy influences the activity of the target protein. These requirements make many pathogenic proteins “undruggable.” Here, we report a strategy to target these undruggable proteins: screening for compounds that directly bind to the undruggable target and rescue disease-relevant phenotypes. These compounds may suppress the target’s pathogenic functions via direct binding to it. We applied this strategy to the mutant HTT protein, which is an undruggable protein that causes Huntington’s disease (HD). We revealed desonide, an FDAapproved drug, as a possible lead compound for HD drug discovery.

A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development

“…Furthermore, polypharmacology is not only a feature of individual molecules but also entire compound classes. Very prominent examples are steranes or sterane-like molecules, such as azadiradione [ 28 ], beclomethasone [ 39 ], betamethasone [ 39 ], budesonide [ 39 ], carbenoxolone [ 117 ], celastrol [ 38 ], deacetoxy-7-oxogedunin [ 29 ], deacetylgedunin [ 29 ], deoxygedunin [ 29 ], desonide [ 118 ], 18β-glycyrrhetinic acid [ 117 ], gugglesterone [ 39 ], hydrocortisone [ 39 ] olesoxime [ 16 , 119 ], ouabain [ 117 ], prednisolone [ 39 ], proscillaridin A [ 117 ], triamcinolone [ 39 ], ursodeoxycholic acid (ursodiol) [ 14 ], and withaferin A [ 120 ]. These address several target categories, such as mitochondrial systems and novel, diverse targets.…”

“…Considering the positive effects of steranes and sterane-like molecules on HD pathology in various HD models [ 14 , 16 , 28 , 29 , 38 , 39 , 117 , 118 , 119 , 120 ], particularly the cholesterol (and phospholipid) transporters ABCA1 (and potentially its functional compensatory counterpart ABCA7 [ 164 , 165 ]) gain relevance in the pathogenesis of HD and potential therapeutic and diagnostic interventions, which warrants further investigations.…”

Distinct binding interactions trigger opposite conformational modulations on pathogenic and wildtype Huntingtin exon 1 proteins

“…101,102 Previous experiments have indicated that the binding sites of both molecules are at the N-terminal domain, where CLR01 destructs the N-terminal amphiphilicity 101 and desonide enhances the polyubiquitination of K 6 . 102 In the case of ispinesib, we have also observed that the binding sites contain residues outside of the polyQ tract, i.e. , not only T 3 in the N-terminal domain but also L 113 in the C-terminal domain.…”

“…Besides ispinesib, two other molecules, CLR01 and desonide, are also able to inhibit the aggregation of pathogenic Httexon-1. 101,102 Previous experiments have indicated that the binding sites of both molecules are at the N-terminal domain, where CLR01 destructs the N-terminal amphiphilicity 101 and desonide enhances the polyubiquitination of K 6 . 102 In the case of ispinesib, we have also observed that the binding sites contain residues outside of the polyQ tract, i.e., not only T 3 in the N-terminal domain but also L 113 in the C-terminal domain.…”

“…101,102 Previous experiments have indicated that the binding sites of both molecules are at the N-terminal domain, where CLR01 destructs the N-terminal amphiphilicity 101 and desonide enhances the polyubiquitination of K 6 . 102 In the case of ispinesib, we have also observed that the binding sites contain residues outside of the polyQ tract, i.e., not only T 3 in the N-terminal domain but also L 113 in the C-terminal domain. Moreover, due to their high flexibility in the apo form, we speculate that the flanking domains also have a high tendency to form the initial binding with ispinesib, and might further induce the compaction of the polyQ tract in a concerted manner.…”