{"doi":"10.1021/acschembio.3c00134","title":"Identification of a Novel Small Molecule That Enhances the Release of Extracellular Vesicles with Immunostimulatory Potency via Induction of Calcium Influx","abstract":"High Resolution Image Download MS PowerPoint Slide Extracellular vesicles (EVs) transfer antigens and immunomodulatory molecules in immunologic synapses as a part of intracellular communication, and EVs equipped with immunostimulatory functions have been utilized for vaccine formulation. Hence, we sought small-molecule compounds that increase immunostimulatory EVs released by antigen-presenting dendritic cells (DCs) for enhancement of vaccine immunogenicity. We previously performed high-throughput screening on a 28K compound library using three THP-1 reporter cell lines with CD63 Turbo-Luciferase, NF-κB, and interferon-sensitive response element (ISRE) reporter constructs, respectively. Because intracellular Ca 2+ elevation enhances EV release, we screened 80 hit compounds and identified compound 634 as a Ca 2+ influx inducer. 634 enhanced EV release in murine bone marrow-derived dendritic cells (mBMDCs) and increased costimulatory molecule expression on the surface of EVs and the parent cells. EVs isolated from 634 -treated mBMDCs induced T cell proliferation in the presence of antigenic peptides. To assess the roles of intracellular Ca 2+ elevation in immunostimulatory EV release, we performed structure–activity relationship (SAR) studies of 634 . The analogues that retained the ability to induce Ca 2+ influx induced more EVs with immunostimulatory properties from mBMDCs than did those that lacked the ability to induce Ca 2+ influx. The levels of Ca 2+ induction of synthesized analogues correlated with the numbers of EVs released and costimulatory molecule expression on the parent cells. Collectively, our study presents that a small molecule, 634, enhances the release of EVs with immunostimulatory potency via induction of Ca 2+ influx. This agent is a novel tool for EV-based immune studies and vaccine development.","journal":"ACS Chemical Biology","year":2023,"id":342530,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9502,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":777807,"name":"Fumi Sato-Kaneko","orcid":null,"position":1,"is_corresponding":false},{"id":777333,"name":"Nikunj M. Shukla","orcid":"0000-0002-5150-7827","position":2,"is_corresponding":false},{"id":441151,"name":"Shiyin Yao","orcid":null,"position":3,"is_corresponding":false},{"id":777806,"name":"Masiel M. Belsuzarri","orcid":null,"position":4,"is_corresponding":false},{"id":281346,"name":"Michael D. Chan","orcid":"0000-0002-5278-6709","position":5,"is_corresponding":false},{"id":777808,"name":"Tetsuya Saito","orcid":null,"position":6,"is_corresponding":false},{"id":777804,"name":"Fitzgerald S. Lao","orcid":null,"position":7,"is_corresponding":false},{"id":1079070,"name":"Helen Kong","orcid":"0000-0002-5203-5497","position":8,"is_corresponding":false},{"id":1079491,"name":"Marina Puffer","orcid":null,"position":9,"is_corresponding":false},{"id":304702,"name":"Karen Messer","orcid":"0000-0002-9298-2413","position":10,"is_corresponding":false},{"id":987132,"name":"Minya Pu","orcid":null,"position":11,"is_corresponding":false},{"id":777336,"name":"Howard B. Cottam","orcid":"0000-0001-7382-0585","position":12,"is_corresponding":false},{"id":440476,"name":"Dennis A. Carson","orcid":"0000-0001-5273-0804","position":13,"is_corresponding":false},{"id":440477,"name":"Tomoko Hayashi","orcid":"0000-0002-9589-8348","position":14,"is_corresponding":false},{"id":1079069,"name":"Y Sako","orcid":"0000-0002-9279-1449","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T01:11:12.506815Z","pmid":"37039433","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":[]}