Emerging Roles of Small-molecule Derivatives in Modulating Neurodegenerative Pathways: From Molecular Targets to...

Area of Science:

• Neuroscience
• Medicinal Chemistry
• Pharmacology

Background:

• Neurodegenerative diseases (Alzheimer's, Parkinson's, ALS, Huntington's) involve progressive neuronal dysfunction.
• Current treatments offer symptomatic relief, lacking disease-modifying capabilities.
• Key pathological mechanisms include protein aggregation, oxidative stress, mitochondrial impairment, and neuroinflammation.

Purpose of the Study:

• To review recent advances in small-molecule drug discovery for neurodegenerative disorders.
• To highlight therapeutic strategies targeting specific pathological pathways and signaling cascades.
• To discuss challenges and future directions in translating these therapeutics into clinical practice.

Main Methods:

• Literature review of medicinal chemistry advancements in neurodegenerative disease therapeutics.
• Analysis of small molecules modulating amyloid-β, tau, α-synuclein, RNA-binding proteins, and NLRP3 inflammasome.
• Discussion of signaling pathways (PI3K/Akt, MAPK/ERK, Nrf2/ARE, Wnt/β-catenin) and drug repurposing.

Main Results:

• Development of small molecules targeting specific pathological pathways offers new therapeutic opportunities.
• Compounds modulating key signaling cascades and neuroinflammatory pathways show potential.
• Novel concepts like multi-target ligands and metal-chelation are emerging.

Conclusions:

• Small-molecule therapeutics hold significant promise for addressing unmet needs in neurodegenerative disease management.
• Overcoming challenges in pharmacokinetics, target selectivity, and blood-brain barrier penetration is crucial.
• Multidisciplinary approaches integrating biomarkers, imaging, and AI are essential for successful clinical translation.