{"doi":"10.1038/s41467-024-49161-9","title":"Broad-spectrum activity against mosquito-borne flaviviruses achieved by a targeted protein degradation mechanism","abstract":"Abstract Viral genetic diversity presents significant challenges in developing antivirals with broad-spectrum activity and high barriers to resistance. Here we report development of proteolysis targeting chimeras (PROTACs) targeting the dengue virus envelope (E) protein through coupling of known E fusion inhibitors to ligands of the CRL4 CRBN E3 ubiquitin ligase. The resulting small molecules block viral entry through inhibition of E-mediated membrane fusion and interfere with viral particle production by depleting intracellular E in infected Huh 7.5 cells. This activity is retained in the presence of point mutations previously shown to confer partial resistance to the parental inhibitors due to decreased inhibitor-binding. The E PROTACs also exhibit broadened spectrum of activity compared to the parental E inhibitors against a panel of mosquito-borne flaviviruses. These findings encourage further exploration of targeted protein degradation as a differentiated and potentially advantageous modality for development of broad-spectrum direct-acting antivirals.","journal":"Nature Communications","year":2024,"id":423361,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":851392,"name":"Zhengnian Li","orcid":"0000-0001-5851-8011","position":1,"is_corresponding":false},{"id":1218455,"name":"Theresia Reindl","orcid":"0000-0001-9633-1899","position":2,"is_corresponding":false},{"id":228753,"name":"Zhixiang He","orcid":"0000-0002-4493-0336","position":3,"is_corresponding":false},{"id":272708,"name":"Xueer Qiu","orcid":null,"position":4,"is_corresponding":false},{"id":1218456,"name":"Ryan P. Golden","orcid":"0009-0004-7113-007X","position":5,"is_corresponding":false},{"id":299772,"name":"Katherine A. Donovan","orcid":"0000-0002-8539-5106","position":6,"is_corresponding":false},{"id":107150,"name":"Adam L. Bailey","orcid":"0000-0002-6560-9680","position":7,"is_corresponding":false},{"id":262829,"name":"Eric S. Fischer","orcid":"0000-0001-7337-6306","position":8,"is_corresponding":false},{"id":226576,"name":"Tinghu Zhang","orcid":"0000-0003-1028-8020","position":9,"is_corresponding":false},{"id":226581,"name":"Nathanael S. Gray","orcid":"0000-0001-5354-7403","position":10,"is_corresponding":false},{"id":258071,"name":"Priscilla L. Yang","orcid":"0000-0001-7456-2557","position":11,"is_corresponding":false},{"id":1218454,"name":"Han‐Yuan Liu","orcid":"0000-0002-9398-6969","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T01:57:56.814994Z","pmid":"38898037","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}