huntingtin

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

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).

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].

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.

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.

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.

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].

Chloroguanabenz (acetate) is an antiprion agent derived from guanabenz, an α2-adrenergic receptor agonist. It inhibits prion formation in vitro in both yeast and mammalian models. Additionally, Chloroguanabenz (acetate) reduces levels of the truncated huntingtin protein derivative Htt48 in HEK293T cells and is used for studying Huntington's disease.

16F16 is a protein disulfide isomerase (PDI) inhibitor.1It inhibits PDI reductase activity in an enzyme assay when used at concentrations ranging from 1 to 100 μg/ml.116F16 reduces PC12 cell apoptosis induced by the misfolded huntingtin protein HTTQ103. It suppresses PDI-dependent mitochondrial outer membrane permeabilization (MOMP) in isolated PC12 cell mitochondria. 16F16 (2, 3, 4, and 10 μM) reduces HTTN90Q73mutant huntingtin-induced medium spinal neuron death and MOMP in rat corticostriatal slices. It also reduces pyramidal neuron death induced by amyloid-β precursor protein (APP) in rat corticostriatal slices. 1.Hoffstrom, B.G., Kaplan, A., Letso, R., et al.Inhibitors of protein disulfide isomerase suppress apoptosis induced by misfolded proteinsNat. Chem. Biol.6(12)900-906(2010)

Chloroguanabenz is an antiprion agent and a derivative of the α2-adrenergic receptor agonist guanabenz . It inhibits prion formation in yeast and mammalian cell-based assays. Chloroguanabenz reduces the levels of both soluble and aggregated forms of the truncated Huntingtin derivative Htt48 in an HEK293T cellular model of Huntington's disease.

Meclocycline is a tetracycline antibiotic with broad antimicrobial activity. Meclocycline inhibits lactate dehydrogenase (LDH) release and cell toxicity induced by expression of htt-N63-148Q, a mutant form of the huntingtin gene, without altering htt-N63-148Q protein levels in PC12 cells.

LC3-mHTT-IN-AN1 is a mHTT-LC3 linker compound that interacts with both mutant huntingtin protein (mHTT) and LC3B. LC3-mHTT-IN-AN1 targeted mHTT to autophagosomes reduces the levels of mHTT in an allele-selective manner in cultured Huntington disease (HD) mouse neurons.

XIE62-1004 is a chemical compound that induces the interaction between p62 and LC3 by binding to the ZZ domain of p62. This interaction promotes p62 self-aggregation and its subsequent interaction with LC3 on autophagosome membranes, thereby facilitating the delivery of cargo proteins to the autophagosome for degradation. XIE62-1004 is effective both in vitro and in vivo, displaying specificity for the wild type of p62 and exhibiting its actions in a concentration- and time-dependent manner. Additionally, it induces the degradation of mutant huntingtin in vitro and can be employed in AUTAC protein degradation systems to trigger autophagy via p62 self-aggregation and LC3 interaction.

Onjisaponin B induces autophagy via the AMPK-mTOR signaling pathway, increases the NGF level and accelerates both the removal of mutant huntingtin and A53T α±-synuclein, it may have potential therapeutic effects on Parkinson disease, Alzheimer disease and Huntington disease.