Huntingtin

Votoplam HCl (PTC-518 HCl) is the hydrochloride form of Votoplam.Votoplam is a systemically acting gene splicing regulator that down-regulates the levels of huntingtin protein, which is primarily used to inhibit Huntington's disease (HD).

Buntanetap ((+)-Phenserine) is an orally active inhibitor of polyneurotoxic proteins (TINAPs) for the study of neurological disorders, endocrine and metabolic disorders, and cardiovascular diseases.

TPE-MI (Tetraphenylethene maleimide) is an aggregation-induced luminescent agent that stains living cells, can be used to capture cysteines in exposed unfolded proteins, and detects protein damage after dihydroartemisinin studies of malaria parasites.

Desonide (Prednacinolone) is a synthetic glucocorticosteroid for topical use, with anti-inflammatory activity. Desonide binds to glucocorticoid receptors in the cytoplasm, and the ligand-receptor complex is translocated as a homodimer into the nucleus, where transcription activation via glucocorticoid response elements within glucocorticoid-responsive genes occur. This agent induces transcription of genes coding for anti-inflammatory proteins, including lipocortin-1, interleukin-10, interleukin-1 receptor antagonist and neutral endopeptidase. Increased synthesis of lipocortin-1 has an inhibitory effect on phospholipase A2, which in turn inhibits the release of arachidonic acid, thereby controlling the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes.

SEN177 shows the potential in the research of Huntington's disease that is a potent inhibitor of glutaminyl cyclase (QPCT) with an IC 50 of 0.013μM for glutaminyl-peptide cyclotransferase-like (QPCTL). The Ki value of SEN177 for human glutaminyl cyclase (hQC) is 20 nM. SEN177 significantly reduces the early stages of mutant HTT oligomerisation and reduces the percentage of neurons with Q80 aggregates [1].

Polyglutamine binding peptide 1 (QBP1) is a peptide inhibitor of polyglutamine (polyQ). It effectively inhibits polyQ protein aggregation in vitro and prevents polyQ-induced cell death in cell cultures.

mHTT-IN-1 (Example 1) is a potent inhibitor of the mutant huntingtin protein (mHTT), which is primarily responsible for Huntington's disease (HD), an inherited autosomal dominant neurodegenerative disorder. This compound effectively reduces mHTT levels with an EC50 of 46 nM.

mHTT-IN-2 (compound 27) is a potent inhibitor of mutant huntingtin protein (mHTT) with an EC50 value of 0.066 μM. It specifically modulates the splicing of HTT RNA exons [49-50], serving as a splicing regulator for the HTT gene. Demonstrating inhibitory effects in vitro and in vivo, mHTT-IN-2 has been tested in human HD stem cells and mouse BACHD models. Additionally, it is applicable in the investigation of branaplam-related peripheral neuropathy [1].

C2-8 is an inhibitor of polyglutamine (polyQ) aggregation with IC50s of 25 and 0.05 μM for recombinant HDQ51 and in PC12 cells, respectively. It also limits polyQ aggregation in organotypic hippocampal slice cultures from R6/2 transgenic mice and reduces neurodegeneration dose-dependently in a Drosophila model of Huntington's disease. C2-8 (100 and 200 mg/kg) decreases huntingtin aggregate size, reduces neuronal atrophy, and enhances motor performance in a rotarod test in the R6/2 transgenic mouse model of Huntington's disease.