Targeting Alpha‐Synuclein Aggregation With Chemical Chaperone IP‐045: An Approach to Parkinson's Disease Therapy

Protein misfolding and aggregation of alpha-synuclein (α-syn) are central to Parkinson's disease (PD). Current therapies provide only symptomatic relief without addressing α-syn aggregation. Chemical chaperones such as 4-phenylbutyrate (4-PBA) and tauroursodeoxycholic acid (TUDCA) show promise but are limited by toxicity and high dosage requirements. This study aimed to develop a safer, more effective multi-target compound to counter α-syn aggregation and related cellular stress. To design, synthesize, and evaluate a novel multi-target chemical chaperone, IP-045, for inhibiting α-syn aggregation and ameliorating PD pathology. A structure-based virtual screen of >11,000 compounds against the α-syn fibril structure (PDB ID: 6UFR) identified four candidates with favorable pharmacokinetics. In vitro aggregation assays and SHSY5Y cell models assessed anti-aggregation activity, cytotoxicity, and modulation of rotenone-induced α-syn expression, oxidative stress, and ER stress. The lead compound, IP-045 (2-Fluorophenyl 3-(1H-indol-3-yl)propanoate), was synthesized and tested in a rotenone-induced PD rat model through behavioral, histological, and molecular analyses. IP-045 strongly inhibited α-syn aggregation in vitro with minimal cytotoxicity. In cell-based assays, it reduced reactive oxygen species, ER stress markers, and α-syn expression. In vivo, IP-045 improved motor coordination, memory, and cognitive performance. Immunohistochemistry showed reduced Ser129-phosphorylated α-syn and restored tyrosine hydroxylase. IP-045 also suppressed apoptotic and pro-inflammatory markers in the substantia nigra, confirming multi-target neuroprotective activity. IP-045 demonstrated favorable anti-aggregation and neuroprotective effects across in vitro and in vivo models, indicating its potential as a promising lead compound with chaperone-like activity for targeting pathological processes associated with PD. Further pharmacokinetic, toxicity, and mechanistic studies are warranted to support its future therapeutic development.