{"doi":"10.1039/d1md00089f","title":"Irreversible inhibition of BoNT/A protease: proximity-driven reactivity contingent upon a bifunctional approach","abstract":"anchor in placing the warhead in an optimal position for reaction with Cys165. Monofunctional control compounds exemplified the necessity of the bifunctional approach, and Cys165 modification was confirmed through high-resolution mass spectrometry (HRMS) and ablation of time-dependent inhibitory activity against a C165A variant. Compounds were also evaluated against BoNT/A-intoxicated motor neuron cells, and their cell toxicity, serum stability, and selectivity against matrix metalloproteinases (MMPs) were characterized. The bifunctional approach allows the use of less intrinsically reactive electrophiles to intercept Cys165, thus expanding the toolbox of potential warheads for selective irreversible BoNT/A LC inhibition. We envision that this dual-targeted strategy is amenable to other metalloproteases that also possess non-catalytic cysteines proximal to the active-site metal center.","journal":"RSC Medicinal Chemistry","year":2021,"id":189966,"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":0.9518,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":741995,"name":"Alexander L. Nielsen","orcid":"0000-0003-1195-0143","position":1,"is_corresponding":false},{"id":753421,"name":"Lucy Lin","orcid":"0000-0001-9546-6919","position":2,"is_corresponding":false},{"id":494468,"name":"Sabine Pellett","orcid":"0000-0001-8186-8810","position":3,"is_corresponding":false},{"id":754075,"name":"Takashi Sugane","orcid":null,"position":4,"is_corresponding":false},{"id":753422,"name":"Margaret E. Olson","orcid":"0000-0003-1865-9615","position":5,"is_corresponding":false},{"id":315641,"name":"Eric A. Johnson","orcid":"0000-0001-8861-0468","position":6,"is_corresponding":false},{"id":516305,"name":"Kim D. Janda","orcid":"0000-0001-6759-4227","position":7,"is_corresponding":false},{"id":741994,"name":"Lewis D. Turner","orcid":"0000-0003-0660-8247","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-18T23:49:22.671571Z","pmid":"34223161","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":[]}