{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T13:03:41Z","timestamp":1779714221674,"version":"3.53.1"},"reference-count":16,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T00:00:00Z","timestamp":1776556800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T00:00:00Z","timestamp":1776556800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Protein misfolding and aggregation of alpha\u2010synuclein (\u03b1\u2010syn) are central to Parkinson's disease (PD). Current therapies provide only symptomatic relief without addressing \u03b1\u2010syn aggregation. Chemical chaperones such as 4\u2010phenylbutyrate (4\u2010PBA) 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\u2010target compound to counter \u03b1\u2010syn aggregation and related cellular stress. To design, synthesize, and evaluate a novel multi\u2010target chemical chaperone, IP\u2010045, for inhibiting \u03b1\u2010syn aggregation and ameliorating PD pathology. A structure\u2010based virtual screen of &gt;11,000 compounds against the \u03b1\u2010syn fibril structure (PDB ID: 6UFR) identified four candidates with favorable pharmacokinetics. In vitro aggregation assays and SHSY5Y cell models assessed anti\u2010aggregation activity, cytotoxicity, and modulation of rotenone\u2010induced \u03b1\u2010syn expression, oxidative stress, and ER stress. The lead compound, IP\u2010045 (2\u2010Fluorophenyl 3\u2010(1H\u2010indol\u20103\u2010yl)propanoate), was synthesized and tested in a rotenone\u2010induced PD rat model through behavioral, histological, and molecular analyses. IP\u2010045 strongly inhibited \u03b1\u2010syn aggregation in vitro with minimal cytotoxicity. In cell\u2010based assays, it reduced reactive oxygen species, ER stress markers, and \u03b1\u2010syn expression. In vivo, IP\u2010045 improved motor coordination, memory, and cognitive performance. Immunohistochemistry showed reduced Ser129\u2010phosphorylated \u03b1\u2010syn and restored tyrosine hydroxylase. IP\u2010045 also suppressed apoptotic and pro\u2010inflammatory markers in the substantia nigra, confirming multi\u2010target neuroprotective activity. IP\u2010045 demonstrated favorable anti\u2010aggregation and neuroprotective effects across in vitro and in vivo models, indicating its potential as a promising lead compound with chaperone\u2010like activity for targeting pathological processes associated with PD. Further pharmacokinetic, toxicity, and mechanistic studies are warranted to support its future therapeutic development.<\/jats:p>","DOI":"10.1002\/ddr.70288","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T06:20:42Z","timestamp":1776666042000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Alpha\u2010Synuclein Aggregation With Chemical Chaperone IP\u2010045: An Approach to Parkinson's Disease Therapy"],"prefix":"10.1002","volume":"87","author":[{"given":"Navpreet","family":"Kaur","sequence":"first","affiliation":[{"name":"Department of Biophysics Panjab University Chandigarh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rimaljot","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Biophysics Panjab University Chandigarh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neelima","family":"Dhingra","sequence":"additional","affiliation":[{"name":"University Institute of Pharmaceutical Sciences Panjab University Chandigarh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2935-7575","authenticated-orcid":false,"given":"Tanzeer","family":"Kaur","sequence":"additional","affiliation":[{"name":"Department of Biophysics Panjab University Chandigarh India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,19]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.23152"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01570-w"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-60327-017-5_14"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jlumin.2014.01.036"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2007.01.043"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2024.116343"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules18066620"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M400255200"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awt192"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2019.116747"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2015.09.023"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4684-5844-2_85"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2014.12.080"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.35.84"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.3934\/Neuroscience.2023017"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph16081162"}],"container-title":["Drug Development Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ddr.70288","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ddr.70288","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ddr.70288","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T12:24:44Z","timestamp":1779711884000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/ddr.70288"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,19]]},"references-count":16,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["10.1002\/ddr.70288"],"URL":"https:\/\/doi.org\/10.1002\/ddr.70288","archive":["Portico"],"relation":{},"ISSN":["0272-4391","1098-2299"],"issn-type":[{"value":"0272-4391","type":"print"},{"value":"1098-2299","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,19]]},"assertion":[{"value":"2025-11-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70288"}}