{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T08:56:48Z","timestamp":1790153808890,"version":"4.0.1"},"reference-count":42,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T00:00:00Z","timestamp":1762128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["24-14-00170"],"award-info":[{"award-number":["24-14-00170"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: This review discusses the development and application of targeted protein degradation strategies, particularly focusing on the ubiquitin\u2013proteasome pathway and PROteolysis-TArgeting Chimeras (PROTAC) technology, for antiviral therapies. Methods\/Results: The synthesis of specific PROTACs exemplifies the potential of this approach to inhibit viral replication. The discussion also covers ongoing efforts to develop broad-spectrum antivirals and explores the limitations of small-molecule ligands, proposing antibody mimetics as a versatile alternative. The review details innovative strategies involving engineered antibody mimetics, termed \u2018diving antibodies\u2019 (DAbs), capable of intracellular delivery and targeting viral proteins within cells. These molecules are engineered using modular nanotransporters to facilitate intracellular delivery. The integration of E3 ligase-binding sites into DAbs enhances their capacity to induce targeted protein degradation, with experimental evidence supporting their efficacy. Conclusions: Overall, the review underscores the potential of combining targeted degradation technologies with innovative delivery systems to create effective antiviral therapies, especially for viruses with limited treatment options.<\/jats:p>","DOI":"10.3390\/pharmaceutics17111420","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T13:47:58Z","timestamp":1762177678000},"page":"1420","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Innovative Strategies for the Targeted Degradation of Viral Proteins: Paving the Way for Next-Generation Therapeutics"],"prefix":"10.3390","volume":"17","author":[{"given":"Alexander S.","family":"Sobolev","sequence":"first","affiliation":[{"name":"Faculty of Biology, Lomonosov Moscow State University, 1-12 Leninskiye Gory St., 119234 Moscow, Russia"},{"name":"Institute of Gene Biology, Russian Academy of Sciences, 34\/5 Vavilov St., 119334 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgii P.","family":"Georgiev","sequence":"additional","affiliation":[{"name":"Institute of Gene Biology, Russian Academy of Sciences, 34\/5 Vavilov St., 119334 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1042\/BJ20141450","article-title":"Targeting Cullin-RING E3 Ubiquitin Ligases for Drug Discovery: Structure, Assembly and Small-Molecule Modulation","volume":"467","author":"Bulatov","year":"2015","journal-title":"Biochem. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1084\/jem.20151531","article-title":"Ubiquitin in the Activation and Attenuation of Innate Antiviral Immunity","volume":"213","author":"Heaton","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Wang, S., Chen, Y., Li, C., Wu, Y., Guo, L., Peng, C., Huang, Y., Cheng, G., and Qin, F.X.F. (2016). TRIM14 Inhibits Hepatitis C Virus Infection by SPRY Domain-Dependent Targeted Degradation of the Viral NS5A Protein. Sci. Rep., 6.","DOI":"10.1038\/srep32336"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1146\/annurev-virology-092917-043323","article-title":"TRIM Proteins and Their Roles in Antiviral Host Defenses","volume":"5","author":"Sparrer","year":"2018","journal-title":"Annu. Rev. Virol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1038\/s41467-022-29690-x","article-title":"An Anti-Influenza A Virus Microbial Metabolite Acts by Degrading Viral Endonuclease PA","volume":"13","author":"Zhao","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Chatterjee, P., Ponnapati, M., Kramme, C., Plesa, A.M., Church, G.M., and Jacobson, J.M. (2020). Targeted Intracellular Degradation of SARS-CoV-2 via Computationally Optimized Peptide Fusions. Commun. Biol., 3.","DOI":"10.1038\/s42003-020-01470-7"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1016\/j.drudis.2020.08.007","article-title":"Could PROTACs Protect Us From COVID-19?","volume":"25","author":"Zhou","year":"2020","journal-title":"Drug Discov. Today"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Nandave, M., and Jain, P. (2024). PROTAC-Mediated Protein Degradation: A Paradigm Shift in Cancer Therapeutics, Springer.","DOI":"10.1007\/978-981-97-5077-1"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41573-021-00371-6","article-title":"PROTAC Targeted Protein Degraders: The Past Is Prologue","volume":"21","author":"Langley","year":"2022","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Reboud-Ravaux, M., and El Amri, C. (2022). COVID-19 Therapies: Protease Inhibitions and Novel Degrader Strategies. Front. Drug Discov., 2.","DOI":"10.3389\/fddsv.2022.892057"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"459","DOI":"10.4155\/fmc-2022-0005","article-title":"Proteolysis Targeting Chimeras in Antiviral Research","volume":"14","author":"Desantis","year":"2022","journal-title":"Future Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3468","DOI":"10.1038\/s41467-019-11429-w","article-title":"Small Molecule Degraders of the Hepatitis C Virus Protease Reduce Susceptibility to Resistance Mutations","volume":"10","author":"Du","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_13","unstructured":"Zhou, H., Wu, S., and Xu, Z. (2021). A Kind of Oseltamivir PROTAC Compound and Its Preparation Method and Application in Anti-Influenza Virus Drug. (CN 112592331 B)."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"100030","DOI":"10.1016\/j.cellin.2022.100030","article-title":"Discovery of Oseltamivir-Based Novel PROTACs as Degraders Targeting Neuraminidase to Combat H1N1 Influenza Virus","volume":"1","author":"Xu","year":"2022","journal-title":"Cell Insight"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7154","DOI":"10.1021\/acs.jmedchem.1c02013","article-title":"Discovery of Pentacyclic Triterpenoid PROTACs as a Class of Effective Hemagglutinin Protein Degraders","volume":"65","author":"Li","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_16","unstructured":"Sch\u00e4ffner, E., and Costard, J. (2025, September 19). Platform-Derived Broad-Spectrum Antivirals A Progress Report on the SPRIND Challenge \u201cBroad-Spectrum Antivirals\u201d. Available online: https:\/\/cms.system.sprind.org\/uploads\/Platform_derived_broad_spectrum_antivirals_449f78c65b.pdf."},{"key":"ref_17","unstructured":"Zhang, K., R\u00f6ske, J., Buddrus, L., Maple, H., Moloney, A., Marsh, G., Cooper, M., Karadogan, B., Chen, Y.-T., and Rox, K. (2025, September 19). MproTAC\u2014New Approach for Development of SARS-CoV-2 Antiviral Drugs. Available online: https:\/\/www.xtal-concepts.com\/wp-content\/uploads\/2024-05-31-Kaixuan-poster.pdf."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6495","DOI":"10.1021\/acs.jmedchem.3c02416","article-title":"Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease","volume":"67","author":"Alugubelli","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1038\/s43856-025-00863-1","article-title":"Targeted Protein Degraders of SARS-CoV-2 Mpro Are More Active than Enzymatic Inhibition Alone with Activity against Nirmatrelvir Resistant Virus","volume":"5","author":"Pan","year":"2025","journal-title":"Commun. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Hahn, F., Hamilton, S.T., Wangen, C., Wild, M., Kicuntod, J., Br\u00fcckner, N., Follett, J.E.L., Herrmann, L., Kheimar, A., and Kaufer, B.B. (2021). Development of a PROTAC-Based Targeting Strategy Provides a Mechanistically Unique Mode of Anti-Cytomegalovirus Activity. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222312858"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1021\/acsmedchemlett.3c00498","article-title":"Development of a GC-376 Based Peptidomimetic PROTAC as a Degrader of 3-Chymotrypsin-like Protease of SARS-CoV-2","volume":"15","author":"Grifagni","year":"2024","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Luo, D., Luo, R., Wang, W., Deng, R., Wang, S., Ma, X., Pu, C., Liu, Y., Zhang, H., and Yu, S. (2024). Discovery of L15 as a Novel Vif PROTAC Degrader with Antiviral Activity against HIV-1. Bioorg. Med. Chem. Lett., 111.","DOI":"10.1016\/j.bmcl.2024.129880"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"100071","DOI":"10.1016\/j.ntm.2025.100071","article-title":"PROTAC-Based Therapeutics for Targeting HPV Oncoproteins in Head and Neck Cancers","volume":"4","author":"Mukerjee","year":"2025","journal-title":"Nano TransMed"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e22145","DOI":"10.1002\/ddr.22145","article-title":"Proteolysis\u2014Targeting Chimeras in Antiviral Therapy: Leveraging Influenza Virus and Exosome\u2014Mediated Delivery for Targeted Protein Degradation and Therapeutic Advancements","volume":"85","author":"Mukerjee","year":"2024","journal-title":"Drug Dev. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3499","DOI":"10.1021\/acsanm.3c04537","article-title":"Synergizing Proteolysis-Targeting Chimeras and Nanoscale Exosome-Based Delivery Mechanisms for HIV and Antiviral Therapeutics","volume":"7","author":"Mukerjee","year":"2024","journal-title":"ACS Appl. Nano Mater."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"47","DOI":"10.32607\/actanaturae.11049","article-title":"The Delivery of Biologically Active Agents into the Nuclei of Target Cells for the Purposes of Translational Medicine","volume":"12","author":"Sobolev","year":"2020","journal-title":"Acta Naturae"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Khramtsov, Y.V., Ulasov, A.V., Slastnikova, T.A., Rosenkranz, A.A., Lupanova, T.N., Georgiev, G.P., and Sobolev, A.S. (2023). Modular Nanotransporters Delivering Biologically Active Molecules to the Surface of Mitochondria. Pharmaceutics, 15.","DOI":"10.20944\/preprints202311.0337.v1"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Khramtsov, Y.V., Ulasov, A.V., Rosenkranz, A.A., Slastnikova, T.A., Lupanova, T.N., Georgiev, G.P., and Sobolev, A.S. (2024). Modular Nanotransporters Deliver Anti-Keap1 Monobody into Mouse Hepatocytes, Thereby Inhibiting Production of Reactive Oxygen Species. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16101345"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1134\/S1607672924601264","article-title":"Modular Nanotransporters Containing Keap1 Monobodies Are Capable of Reducing the Toxic Effect of Acetaminophen on the Liver of Mice","volume":"521","author":"Khramtsov","year":"2025","journal-title":"Dokl. Biochem. Biophys."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1134\/S1607672923700114","article-title":"Intracellular Delivery of an Antibody-Like Molecule Capable of Inhibiting c-Myc","volume":"509","author":"Lupanova","year":"2023","journal-title":"Dokl. Biochem. Biophys."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"S63","DOI":"10.1134\/S1607672923700709","article-title":"Quantitative Description of the N-Protein of the SARS-CoV-2 Virus Degradation in Cells Stably Expressing It under the Influence of New Modular Nanotransporters","volume":"513","author":"Khramtsov","year":"2024","journal-title":"Dokl. Biochem. Biophys."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Khramtsov, Y.V., Ulasov, A.V., Lupanova, T.N., Slastnikova, T.A., Rosenkranz, A.A., Bunin, E.S., Georgiev, G.P., and Sobolev, A.S. (2024). Intracellular Degradation of SARS-CoV-2 N-Protein Caused by Modular Nanotransporters Containing Anti-N-Protein Monobody and a Sequence That Recruits the Keap1 E3 Ligase. Pharmaceutics, 16.","DOI":"10.20944\/preprints202311.0257.v1"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"S60","DOI":"10.1134\/S1607672923700710","article-title":"Modular Nanotransporters Capable of Causing Intracellular Degradation of the N-Protein of the SARS-CoV-2 Virus in A549 Cells with Temporary Expression of This Protein Fused with a Fluorescent Protein MRuby3","volume":"513","author":"Khramtsov","year":"2024","journal-title":"Dokl. Biochem. Biophys."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1134\/S1607672924601136","article-title":"Optimization of A549 Cell Transfection Efficiency with a Plasmid Encoding the N-Protein of the SARS-CoV-2 Virus","volume":"521","author":"Khramtsov","year":"2025","journal-title":"Dokl. Biochem. Biophys."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1134\/S1607672922600233","article-title":"Modular Nanotransporters Capable of Binding to SARS-CoV-2 Virus Nucleocapsid Protein in Target Cells","volume":"510","author":"Khramtsov","year":"2023","journal-title":"Dokl. Biochem. Biophys."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.sbi.2020.01.015","article-title":"Monobodies as Enabling Tools for Structural and Mechanistic Biology","volume":"60","author":"Hantschel","year":"2020","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1038\/s41556-021-00710-0","article-title":"Targeting Liquid\u2013Liquid Phase Separation of SARS-CoV-2 Nucleocapsid Protein Promotes Innate Antiviral Immunity by Elevating MAVS Activity","volume":"23","author":"Wang","year":"2021","journal-title":"Nat. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1038\/s41467-023-38015-5","article-title":"Large-Scale Phage-Based Screening Reveals Extensive Pan-Viral Mimicry of Host Short Linear Motifs","volume":"14","author":"Simonetti","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.tibs.2023.01.004","article-title":"Interaction Modules That Impart Specificity to Disordered Protein","volume":"48","author":"Cermakova","year":"2023","journal-title":"Trends Biochem. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1134\/S1607672922020077","article-title":"Among antibody-like molecules, monobodies, able to interact with nucleocapsid protein of SARS-CoV virus, there are monobodies with high affinity to nucleocapsid protein of SARS-CoV-2 virus","volume":"503","author":"Khramtsov","year":"2022","journal-title":"Dokl. Biochem. Biophys."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1021\/acs.jmedchem.2c01791","article-title":"Degrader\u2013antibody conjugates: Emerging new modality","volume":"66","author":"Hong","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5791","DOI":"10.1073\/pnas.1920251117","article-title":"BioPROTACs as Versatile Modulators of Intracellular Therapeutic Targets Including Proliferating Cell Nuclear Antigen (PCNA)","volume":"117","author":"Lim","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/11\/1420\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T14:02:58Z","timestamp":1762178578000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/11\/1420"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,3]]},"references-count":42,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["pharmaceutics17111420"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17111420","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,3]]}}}