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 diseasemodifying 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. In fact, Food and Drug Administration (FDA) approved two synthetic small-molecule VMAT2 inhibitors, 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 mechanism/s.

Keywords: Huntington’s disease; Natural products; drug discovery; huntingtin (HTT); molecules; neuroprotective mechanisms; therapeutic interventions.

Fig. (1)

Schematic diagram depicting the sequel of events/mechanisms in HD pathogenesis. mHTT (PDB: 6X9O) via dysregulation of various processes like proteasomal and autophagic degradation, mitochondrial dysfunction and oxidative stress, neuroinflammation, synaptic and axonal transport deregulation, genomic instability, transcriptional dysfunction, and gut dysbiosis results in neurodegeneration and HD pathogenesis. Abbreviations: MSN, medium spiny neurons; HD, Huntington’s disease; HTT, huntingtin gene; mHTT, mutant Huntington protein. Figure prepared using Biorender software.

Fig. (2)

Schematic diagram depicting the numerous stressors, such as mitochondrial oxidative stress, by the activation of Keap1/Nrf2/ARE pathway, to promote neurohormetic response via transcriptional upregulation of cytoprotective proteins and prevent neuronal injury and death. Figure prepared using Biorender software.

Fig. (3)

Chemical structure of FDA-approved drugs to manage chorea associated with HD.

Fig. (4)

Structures of synthetic small-molecule-based clinical candidates to manage HD.

Fig. (5)

Overview of the putative neuroprotective mechanisms of natural products against HD. Figure was prepared by using Biorender software.

Fig. (6)

Clinical natural products with anti-oxidant and anti-inflammatory activities to manage HD.

Fig. (7)

Preclinical natural products with anti-oxidant and anti-inflammatory activities to manage HD.

Fig. (8)

Natural products to manage HD (A) by inhibiting mHTT aggregation, excitotoxicity, and RNA splicing; (B) by improving mitochondrial functions and BDNF synthesis; and (C) by modulating apoptosis and autophagy.

Fig. (9)

Natural products promote neurohormetic response by activation of the Keap1/Nrf2/ARE signalling pathway. Figure prepared using Biorender software.