The Emerging Landscape of Natural Small-molecule Therapeutics for Huntington’s Disease

Abstract: Huntington’s disease (HD) is a rare and fatal neurodegenerative disorder with no disease modifying therapeutics. HD is characterized by extensive neuronal loss and is caused by the inherited expansion of the huntingtin (HTT) gene that encodes a toxic mutant HTT (mHTT) protein having expanded polyglutamine (polyQ) residues. Current HD therapeutics only offer symptomatic relief. Infact, Food and Drug Administration (FDA) approved two synthetic small-molecule VMAT2 inhibi-tors, tetrabenazine (1) and deutetrabenazine (2), for managing HD chorea and various other diseases in clinical trials. Therefore, the landscape of drug discovery programs for HD is evolving to discover disease-modifying HD therapeutics. Likewise, numerous natural products are being evaluated at different stages of clinical development and have shown the potential to ameliorate HD pathology. The inherent anti-inflammatory and antioxidant properties of natural products mitigate the mHTT-induced oxidative stress and neuroinflammation, improve mitochondrial functions, and augment the anti-apoptotic and pro-autophagic mechanisms for increased survival of neurons in HD. In this review, we have discussed HD pathogenesis and summarized the anti-HD clinical and pre-clinical natural products, focusing on their therapeutic effects and neuroprotective mechanisms.