{"doi":"10.1039/d3ra00426k","title":"A covalent inhibitor targeting the papain-like protease from SARS-CoV-2 inhibits viral replication","abstract":"Covalent inhibitors of the papain-like protease (PLpro) from SARS-CoV-2 have great potential as antivirals, but their non-specific reactivity with thiols has limited their development. In this report, we performed an 8000 molecule electrophile screen against PLpro and identified an α-chloro amide fragment, termed compound 1, which inhibited SARS-CoV-2 replication in cells, and also had low non-specific reactivity with thiols. Compound 1 covalently reacts with the active site cysteine of PLpro, and had an IC50 of 18 μM for PLpro inhibition. Compound 1 also had low non-specific reactivity with thiols and reacted with glutathione 1-2 orders of magnitude slower than other commonly used electrophilic warheads. Finally, compound 1 had low toxicity in cells and mice and has a molecular weight of only 247 daltons and consequently has great potential for further optimization. Collectively, these results demonstrate that compound 1 is a promising lead fragment for future PLpro drug discovery campaigns.","journal":"RSC Advances","year":2023,"id":352459,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"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":1098349,"name":"Albert Vallejo Gracia","orcid":null,"position":1,"is_corresponding":false},{"id":320284,"name":"Joachim Justad Røise","orcid":"0000-0002-1794-7570","position":2,"is_corresponding":false},{"id":255566,"name":"Lydia Boike","orcid":"0000-0002-6495-8942","position":3,"is_corresponding":false},{"id":227698,"name":"Kristoffer E. Leon","orcid":"0000-0003-2424-0458","position":4,"is_corresponding":false},{"id":108135,"name":"Ursula Schulze‐Gahmen","orcid":"0000-0003-3919-4474","position":5,"is_corresponding":false},{"id":967287,"name":"Michael R. Stentzel","orcid":null,"position":6,"is_corresponding":false},{"id":565936,"name":"Teena Bajaj","orcid":"0000-0003-4966-4214","position":7,"is_corresponding":false},{"id":966889,"name":"Dake Chen","orcid":"0000-0002-1966-1461","position":8,"is_corresponding":false},{"id":500740,"name":"I-Che Li","orcid":"0000-0002-5819-8094","position":9,"is_corresponding":false},{"id":311049,"name":"Maomao He","orcid":"0000-0002-7682-1142","position":10,"is_corresponding":false},{"id":648407,"name":"Kamyar Behrouzi","orcid":"0000-0002-3800-2197","position":11,"is_corresponding":false},{"id":1098350,"name":"Zahra Khodabakhshi","orcid":null,"position":12,"is_corresponding":false},{"id":34058,"name":"Daniel K. Nomura","orcid":"0000-0003-1614-8360","position":13,"is_corresponding":false},{"id":263138,"name":"Mohammad R. K. Mofrad","orcid":"0000-0001-7004-4859","position":14,"is_corresponding":false},{"id":107216,"name":"G. Renuka Kumar","orcid":"0000-0001-6090-3285","position":15,"is_corresponding":false},{"id":103701,"name":"Mélanie Ott","orcid":"0000-0002-5697-1274","position":16,"is_corresponding":false},{"id":235839,"name":"Niren Murthy","orcid":"0000-0002-7815-7337","position":17,"is_corresponding":false},{"id":492016,"name":"Hesong Han","orcid":"0000-0001-5545-5238","position":0,"is_corresponding":true}],"reference_count":27,"raw_metadata":null,"created_at":"2026-07-19T01:12:50.107998Z","pmid":"37025664","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":[]}