{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T13:12:46Z","timestamp":1788441166432,"version":"build-2803163510"},"reference-count":92,"publisher":"American Chemical Society (ACS)","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","award":["BT\/PR32907\/MED\/122\/227\/2019"],"award-info":[{"award-number":["BT\/PR32907\/MED\/122\/227\/2019"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Parkinson\u2019s disease (PD) is characterized by the pathological aggregation of \u03b1-synuclein (\u03b1-syn) into \u03b2-sheet-rich fibrils, contributing to neuronal toxicity and oxidative stress. In this study, we investigated the inhibitory and disaggregating effects of Triprolidine (TC) on \u03b1-syn fibrillation through a combined experimental and computational approach. Biophysical assays, including ThT assay, DLS, and ANS assays, demonstrated that TC inhibits \u03b1-syn fibrillation in a concentration-dependent manner (IC50 \u2248 255 \u03bcM), disrupts preformed fibrils, and maintains the protein\u2019s native form. CD data further revealed that TC prevents the transition of \u03b1-syn to its toxic \u03b2-sheet-rich form and facilitates partial structural reversal during disaggregation. To elucidate the molecular mechanism of inhibition, we performed all-atom molecular dynamics (MD) simulations followed by Markov State Model (MSM) construction. The simulations revealed that TC binding remodels the conformational landscape of \u03b1-syn by stabilizing compact, disordered states and reducing the population of \u03b2-sheet-prone intermediates, particularly in the aggregation-prone NAC region. MSM analysis identified metastable states with diminished aggregation potential and reduced inter-residue contact probability, offering mechanistic insights into how TC interferes with early nucleation events. TC attenuates seeded fibrillation in a concentration-dependent manner too. Complementary cellular assays, including MTT and hemolytic assays, confirmed a significant reduction in \u03b1-syn-induced cytotoxicity upon TC treatment, with a decrease in ROS levels as confirmed by the DCFH-DA assay. Together, these findings demonstrate that TC modulates both the structural dynamics and functional toxicity of \u03b1-synuclein, and highlight its potential as a promising chemical modulator for further investigation in PD-related protein aggregation.<\/jats:p>","DOI":"10.1021\/acs.biochem.6c00571","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T18:01:32Z","timestamp":1788285692000},"source":"Crossref","is-referenced-by-count":0,"title":["Triprolidine\nInterferes with \u03b1-Synuclein\nFibrillation and Remodels Aggregate Structure via Conformational Modulation"],"prefix":"10.1021","author":[{"given":"Md Nadir","family":"Hassan","sequence":"first","affiliation":[{"name":"Aligarh Muslim University , , , ,","place":["Aligarh, UP, India, 202002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murtaza","family":"Hussain","sequence":"additional","affiliation":[{"name":"Aligarh Muslim University , , , ,","place":["Aligarh, UP, India, 202002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5236-9905","authenticated-orcid":true,"given":"Faisal","family":"Nabi","sequence":"additional","affiliation":[{"name":"Aligarh Muslim University , , , ,","place":["Aligarh, UP, India, 202002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devendra","family":"Singh","sequence":"additional","affiliation":[{"name":"Aligarh Muslim University , , , ,","place":["Aligarh, UP, India, 202002"]},{"name":"PSL University, INSERM, CNRS , , ,","place":["Paris, France, 75005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumbul","family":"Yasmeen","sequence":"additional","affiliation":[{"name":"Aligarh Muslim University , , , ,","place":["Aligarh, UP, India, 202002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md Sharique","family":"Zafar","sequence":"additional","affiliation":[{"name":"Aligarh Muslim University , , , ,","place":["Aligarh, UP, India, 202002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irum","family":"Rizvi","sequence":"additional","affiliation":[{"name":"Aligarh Muslim University , , , ,","place":["Aligarh, UP, India, 202002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed Mohammad","family":"Zakariya","sequence":"additional","affiliation":[{"name":"Aligarh Muslim University , , , ,","place":["Aligarh, UP, India, 202002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waseem A.","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"Aligarh Muslim University , , , ,","place":["Aligarh, UP, India, 202002"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4037-5857","authenticated-orcid":true,"given":"Vladimir N.","family":"Uversky","sequence":"additional","affiliation":[{"name":"University of South Florida , , , ,","place":["Tampa, Florida, United States, 33612"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9965-8982","authenticated-orcid":true,"given":"Rizwan Hasan","family":"Khan","sequence":"additional","affiliation":[{"name":"Aligarh Muslim University , , , ,","place":["Aligarh, UP, India, 202002"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"2026090308155857300_cit1","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1016\/S0896-6273(03)00568-3","article-title":"Parkinson\u2019s Disease: Mechanisms and Models","volume":"39","author":"Dauer","year":"2003","journal-title":"Neuron."},{"key":"2026090308155857300_cit2","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/bpa.12344","article-title":"Lewy Bodies and the\nMechanisms of\nNeuronal Cell Death in Parkinson\u2019s Disease and Dementia with\nLewy Bodies","volume":"27","author":"Power","year":"2017","journal-title":"Brain Pathol."},{"issue":"1","key":"2026090308155857300_cit3","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-023-00378-6","article-title":"Role of\nDopamine in the Pathophysiology of Parkinson\u2019s Disease","volume":"12","author":"Zhou","year":"2023","journal-title":"Transl. 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