{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T02:50:49Z","timestamp":1788058249006,"version":"build-2784847793"},"reference-count":49,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T00:00:00Z","timestamp":1764720000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01AG060149"],"award-info":[{"award-number":["R01AG060149"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"UCLA Parkinson Disease Seed Grant Program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>One of the most important events in the pathogenesis of Parkinson\u2019s disease and related disorders is the formation of abnormal fibrils via the aggregation of \u03b1-synuclein (\u03b1-syn) with \u03b2-sheet-rich organization. The use of Cryo-EM has uncovered different polymorphs of the fibrils, each having unique structural interfaces, which has made the design of inhibitors even more challenging. Here, a structure-guided framework incorporating AI-assisted peptide generation was set up with the objective of targeting the conserved \u03b2-sheet motifs that are present in various forms of \u03b1-syn fibrils. The ProteinMPNN, then, AlphaFold-Multimer, and PepMLM were employed to create short peptides that would interfere with the growth of the fibrils. The two selected candidates, T1 and S1, showed a significant inhibition of \u03b1-syn fibrillation, as measured by a decrease in the ThT fluorescence and the generation of either amorphous or fragmented aggregates. The inhibitory potency of the peptides was in line with the predicted interface energies. This research work illustrates that the integration of cryo-EM structural knowledge with the computational design method leads to the quick discovery of the wide-spectrum peptide inhibitors, which is a good strategy for the precision treatment of neurodegenerative diseases.<\/jats:p>","DOI":"10.3390\/cells14231921","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T15:02:48Z","timestamp":1764774168000},"page":"1921","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["AI-Guided Dual Strategy for Peptide Inhibitor Design Targeting Structural Polymorphs of \u03b1-Synuclein Fibrils"],"prefix":"10.3390","volume":"14","author":[{"given":"Jinfang","family":"Duan","sequence":"first","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA"},{"name":"School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6443-6407","authenticated-orcid":false,"given":"Chuanqi","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA"},{"name":"Departments of Biological Chemistry and Chemistry and Biochemistry, UCLA-DOE Institute, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2741","DOI":"10.1007\/s12035-020-01913-6","article-title":"Polymorphic alpha-Synuclein Strains Modified by Dopamine and Docosahexaenoic Acid Interact Differentially with Tau Protein","volume":"57","author":"Sengupta","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Shimogawa, M., Li, M.H., Park, G.S.H., Ramirez, J., Lee, H., Watson, P.R., Sharma, S., Lin, Z., Peng, C., and Lee, V.M. (2025). Investigation of All Disease-Relevant Lysine Acetylation Sites in alpha-Synuclein Enabled by Non-canonical Amino Acid Mutagenesis. bioRxiv.","DOI":"10.1101\/2025.01.21.634178"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3913","DOI":"10.1016\/j.jmb.2019.07.001","article-title":"Structural Insights into alpha-Synuclein Fibril Polymorphism: Effects of Parkinson\u2019s Disease-Related C-Terminal Truncations","volume":"431","author":"Ni","year":"2019","journal-title":"J. Mol. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1038\/s41422-020-0299-4","article-title":"Cryo-EM structure of full-length alpha-synuclein amyloid fibril with Parkinson\u2019s disease familial A53T mutation","volume":"30","author":"Sun","year":"2020","journal-title":"Cell Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6499","DOI":"10.1038\/s44318-025-00573-3","article-title":"Structural polymorphism of alpha-synuclein fibrils alters the pathway of Hsc70-mediated disaggregation","volume":"44","author":"Jager","year":"2025","journal-title":"EMBO J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/nrn3549","article-title":"Parkinson\u2019s disease dementia: Convergence of alpha-synuclein, tau and amyloid-beta pathologies","volume":"14","author":"Irwin","year":"2013","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/nm.4269","article-title":"Alpha-synuclein toxicity in neurodegeneration: Mechanism and therapeutic strategies","volume":"23","author":"Wong","year":"2017","journal-title":"Nat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Sun, C., Zhou, K., DePaola, P.t.d, Shin, W.S., Hillyer, T., Sawaya, M.R., Zhu, R., Peng, C., Zhou, Z.H., and Jiang, L. (2023). Cryo-EM structure of amyloid fibril formed by alpha-synuclein hereditary A53E mutation reveals a distinct protofilament interface. J. Biol. Chem., 299.","DOI":"10.1016\/j.jbc.2023.104566"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7604","DOI":"10.1523\/JNEUROSCI.0297-11.2011","article-title":"Induction of intracellular tau aggregation is promoted by alpha-synuclein seeds and provides novel insights into the hyperphosphorylation of tau","volume":"31","author":"Waxman","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1016\/j.neuron.2025.03.019","article-title":"Fibril fuzzy coat is important for alpha-synuclein pathological transmission activity","volume":"113","author":"Han","year":"2025","journal-title":"Neuron"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1002\/1873-3468.15048","article-title":"Cryo-EM structure of a novel alpha-synuclein filament subtype from multiple system atrophy","volume":"599","author":"Yan","year":"2025","journal-title":"FEBS Lett."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Enomoto, M., Martinez-Valbuena, I., Forrest, S.L., Xu, X., Munhoz, R.P., Li, J., Rogaeva, E., Lang, A.E., and Kovacs, G.G. (2024). Lewy-MSA hybrid fold drives distinct neuronal alpha-synuclein pathology. bioRxiv.","DOI":"10.1101\/2024.11.21.624748"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e56825","DOI":"10.7554\/eLife.56825","article-title":"Alpha-synuclein strains that cause distinct pathologies differentially inhibit proteasome","volume":"9","author":"Suzuki","year":"2020","journal-title":"eLife"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1042\/BCJ20240602","article-title":"Structural commonalities determined by physicochemical principles in the complex polymorphism of the amyloid state of proteins","volume":"482","author":"Errico","year":"2025","journal-title":"Biochem. J."},{"key":"ref_15","first-page":"444","article-title":"The Contribution of Tau, Amyloid-Beta and Alpha-Synuclein Pathology to Dementia in Lewy Body Disorders","volume":"8","author":"Irwin","year":"2018","journal-title":"J. Alzheimer\u2019s Dis. Park."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Vasili, E., Dominguez-Meijide, A., and Outeiro, T.F. (2019). Spreading of alpha-Synuclein and Tau: A Systematic Comparison of the Mechanisms Involved. Front. Mol. Neurosci., 12.","DOI":"10.3389\/fnmol.2019.00107"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2946","DOI":"10.1111\/ejn.14699","article-title":"Update on the association between alpha-synuclein and tau with mitochondrial dysfunction: Implications for Parkinson\u2019s disease","volume":"53","author":"Feng","year":"2021","journal-title":"Eur. J. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"De Luca, L., Vittorio, S., Pena-Diaz, S., Pitasi, G., Fornt-Sune, M., Bucolo, F., Ventura, S., and Gitto, R. (2022). Ligand-Based Discovery of a Small Molecule as Inhibitor of alpha-Synuclein Amyloid Formation. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232314844"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"28282","DOI":"10.1021\/jacs.4c08869","article-title":"Inhibitor Development for alpha-Synuclein Fibril\u2019s Disordered Region to Alleviate Parkinson\u2019s Disease Pathology","volume":"146","author":"Zhang","year":"2024","journal-title":"J. Am. Chem. Soc."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Zhang, S., Liu, K., Li, D., and Liu, C. (2025). Rising Stars: Molecular Mechanisms and Chemical Interventions of alpha-Synuclein Amyloid Aggregation in Parkinson\u2019s Disease. J. Mol. Biol., 437.","DOI":"10.1016\/j.jmb.2025.169475"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"102522","DOI":"10.1016\/j.npep.2025.102522","article-title":"PQK7: A novel peptide inhibitor targeting alpha-synuclein fibrillogenesis in Parkinson\u2019s disease","volume":"111","author":"Motamedi","year":"2025","journal-title":"Neuropeptides"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1093\/molehr\/gau054","article-title":"A peptide inhibitor of synuclein-gamma reduces neovascularization of human endometriotic lesions","volume":"20","author":"Edwards","year":"2014","journal-title":"Mol. Hum. Reprod."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kazmirchuk, T.D.D., Wang, J., Bury, L., Falcinelli, E., Bradbury-Jost, C., Koziar, A., Al-Gafari, M., Takallou, S., Willmore, W.G., and Dehne, F. (2025). Developing an AI-Generated Peptide Targeting Platelet-type von Willebrand Disease. Blood Adv.","DOI":"10.1182\/bloodadvances.2025017674"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kong, X., Jiao, R., Lin, H., Guo, R., Huang, W., Ma, W.Y., Wang, Z., Liu, Y., and Ma, J. (2025). Peptide design through binding interface mimicry with PepMimic. Nat. Biomed. Eng.","DOI":"10.1038\/s41551-025-01507-4"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Chen, L.T., Quinn, Z., Dumas, M., Peng, C., Hong, L., Lopez-Gonzalez, M., Mestre, A., Watson, R., Vincoff, S., and Zhao, L. (2025). Target sequence-conditioned design of peptide binders using masked language modeling. Nat. Biotechnol.","DOI":"10.1038\/s41587-025-02761-2"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ferreira, T., Pereira, F., Goncalves, F., da Costa, A., Cavaco-Paulo, A., and Castro, T.G. (2025). AI, docking, and molecular dynamics to track the binding of structural peptides to different keratin models. Int. J. Biol. Macromol., 317.","DOI":"10.1016\/j.ijbiomac.2025.144813"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Liu, D., Jiang, Y., Ma, B., and Li, L. (2025). Structure-based artificial intelligence-aided design of MYC-targeting degradation drugs for cancer therapy. Biochem. Biophys. Res. Commun., 766.","DOI":"10.1016\/j.bbrc.2025.151870"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e2412926","DOI":"10.1002\/advs.202412926","article-title":"CPL-Diff: A Diffusion Model for De Novo Design of Functional Peptide Sequences with Fixed Length","volume":"12","author":"Luo","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s13024-023-00675-8","article-title":"Peptide-based approaches to directly target alpha-synuclein in Parkinson\u2019s disease","volume":"18","author":"Allen","year":"2023","journal-title":"Mol. Neurodegener."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Sun, C., Zhou, K., DePaola, P.t., Li, C., Lee, V.M.Y., Zhou, Z.H., Peng, C., and Jiang, L. (2025). Structural basis of a distinct alpha-synuclein strain that promotes tau inclusion in neurons. J. Biol. Chem., 301.","DOI":"10.1016\/j.jbc.2025.108351"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3609","DOI":"10.1038\/s41467-018-05971-2","article-title":"Cryo-EM of full-length alpha-synuclein reveals fibril polymorphs with a common structural kernel","volume":"9","author":"Li","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e36402","DOI":"10.7554\/eLife.36402","article-title":"Cryo-EM structure of alpha-synuclein fibrils","volume":"7","author":"Taylor","year":"2018","journal-title":"eLife"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1038\/s41422-018-0075-x","article-title":"Amyloid fibril structure of alpha-synuclein determined by cryo-electron microscopy","volume":"28","author":"Li","year":"2018","journal-title":"Cell Res."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Lim, K.H. (2019). Diverse Misfolded Conformational Strains and Cross-seeding of Misfolded Proteins Implicated in Neurodegenerative Diseases. Front. Mol. Neurosci., 12.","DOI":"10.3389\/fnmol.2019.00158"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"fcaa090","DOI":"10.1093\/braincomms\/fcaa090","article-title":"Differential cross-seeding properties of tau and alpha-synuclein in mouse models of tauopathy and synucleinopathy","volume":"2","author":"Williams","year":"2020","journal-title":"Brain Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1002\/2211-5463.13110","article-title":"Seeded assembly in vitro does not replicate the structures of alpha-synuclein filaments from multiple system atrophy","volume":"11","author":"Lovestam","year":"2021","journal-title":"FEBS Open Bio"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"20305","DOI":"10.1073\/pnas.1922741117","article-title":"Parkinson\u2019s disease-related phosphorylation at Tyr39 rearranges alpha-synuclein amyloid fibril structure revealed by cryo-EM","volume":"117","author":"Zhao","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/s41586-020-2317-6","article-title":"Structures of alpha-synuclein filaments from multiple system atrophy","volume":"585","author":"Schweighauser","year":"2020","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e2012435118","DOI":"10.1073\/pnas.2012435118","article-title":"Wild-type alpha-synuclein inherits the structure and exacerbated neuropathology of E46K mutant fibril strain by cross-seeding","volume":"118","author":"Long","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1007\/s00401-023-02657-y","article-title":"Distinct tau and alpha-synuclein molecular signatures in Alzheimer\u2019s disease with and without Lewy bodies and Parkinson\u2019s disease with dementia","volume":"147","author":"Deshayes","year":"2024","journal-title":"Acta Neuropathol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Sanchez, J.C., Pierson, J., Borcik, C.G., Rienstra, C.M., and Wright, E.R. (2024). High-Resolution Cryo-EM Structure Determination of alpha-synuclein\u2014A Prototypical Amyloid Fibril. bioRxiv.","DOI":"10.1101\/2024.09.18.613698"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e93562","DOI":"10.7554\/eLife.93562.4","article-title":"On the pH-dependence of alpha-synuclein amyloid polymorphism and the role of secondary nucleation in seed-based amyloid propagation","volume":"12","author":"Frey","year":"2024","journal-title":"eLife"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Cullinane, P.W., Yang, Y., Chelban, V., Goh, Y.Y., Ebanks, K., Curless, T., Wrigley, S., de Pablo-Fernandez, E., Holton, J., and Peak-Chew, S. (2025). Identical Seeding Characteristics and Cryo-EM Filament Structures in FTLD-Synuclein and Typical Multiple System Atrophy. Neuropathol. Appl. Neurobiol., 51.","DOI":"10.1111\/nan.70013"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1126\/science.add2187","article-title":"Robust deep learning-based protein sequence design using ProteinMPNN","volume":"378","author":"Dauparas","year":"2022","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"baad084","DOI":"10.1093\/database\/baad084","article-title":"aSynPEP-DB: A database of biogenic peptides for inhibiting alpha-synuclein aggregation","volume":"2023","author":"Barcenas","year":"2023","journal-title":"Database"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.it.2025.02.013","article-title":"Using structure-function information from IFN-gamma-binding proteins and biased agonists to uncouple immunostimulatory and immunosuppressive activities","volume":"46","year":"2025","journal-title":"Trends Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"100149","DOI":"10.1016\/j.bbadva.2025.100149","article-title":"Protein recognition methods for diagnostics and therapy","volume":"7","author":"Montoya","year":"2025","journal-title":"BBA Adv."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Mohan Kumar, D., and Talwar, P. (2025). Amyloid-beta, Tau, and alpha-Synuclein Protein Interactomes as Therapeutic Targets in Neurodegenerative Diseases. Cell. Mol. Neurobiol., 45.","DOI":"10.1007\/s10571-025-01604-7"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/23\/1921\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T05:28:49Z","timestamp":1764912529000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/23\/1921"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,3]]},"references-count":49,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["cells14231921"],"URL":"https:\/\/doi.org\/10.3390\/cells14231921","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,3]]}}}