{"doi":"10.1101/2021.02.05.429937","title":"Post-infection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection","abstract":"Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a serious global public health threat. The 3C-like protease (3CLpro) is a virus protease encoded by SARS-CoV-2, which is essential for virus replication. We have previously reported a series of small molecule 3CLpro inhibitors effective for inhibiting replication of human coronaviruses including SARS-CoV-2 in cell culture and in animal models. Here we generated a series of deuterated variants of a 3CLpro inhibitor, GC376, and evaluated the antiviral effect against SARS-CoV-2. The deuterated GC376 displayed potent inhibitory activity against SARS-CoV-2 in the enzyme and the cell-based assays. The K18-hACE2 mice develop mild to lethal infection commensurate with SARS-CoV-2 challenge doses and was proposed as a model for efficacy testing of antiviral agents. We treated lethally infected mice with a deuterated derivative of GC376. Treatment of K18-hACE2 mice at 24 hr post infection with a derivative (compound 2) resulted in increased survival of mice compared to vehicle-treated mice. Lung virus titers were decreased, and histopathological changes were ameliorated in compound 2-treated mice compared to vehicle-treated mice. Structural investigation using high-resolution crystallography illuminated binding interactions of 3CLpro of SARS-CoV-2 and SARS-CoV with deuterated variants of GC376. Taken together, deuterated GC376 variants have excellent potential as antiviral agents against SARS-CoV-2.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":213527,"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":19,"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":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":805563,"name":"Jian Zhang","orcid":"0000-0002-1896-0195","position":1,"is_corresponding":false},{"id":235568,"name":"Krishani Dinali Perera","orcid":"0000-0002-3778-4975","position":2,"is_corresponding":false},{"id":360688,"name":"Lok-Yin Roy Wong","orcid":"0000-0002-0727-8289","position":3,"is_corresponding":false},{"id":227015,"name":"David K. Meyerholz","orcid":"0000-0003-1552-3253","position":4,"is_corresponding":false},{"id":408117,"name":"Harry Nhat Nguyen","orcid":null,"position":5,"is_corresponding":false},{"id":235570,"name":"M.M. Kashipathy","orcid":"0000-0003-0435-989X","position":6,"is_corresponding":false},{"id":235571,"name":"K.P. Battaile","orcid":"0000-0003-0833-3259","position":7,"is_corresponding":false},{"id":235572,"name":"Scott Lovell","orcid":"0000-0002-3215-4472","position":8,"is_corresponding":false},{"id":235567,"name":"Yunjeong Kim","orcid":"0000-0002-2977-4400","position":9,"is_corresponding":false},{"id":77538,"name":"Stanley Perlman","orcid":"0000-0003-4213-2354","position":10,"is_corresponding":false},{"id":235573,"name":"William C. Groutas","orcid":"0000-0001-5248-7912","position":11,"is_corresponding":false},{"id":235574,"name":"Kyeong‐Ok Chang","orcid":"0000-0002-4435-3751","position":12,"is_corresponding":false},{"id":407008,"name":"Chamandi S. Dampalla","orcid":"0000-0002-8199-2376","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-18T23:52:36.886828Z","pmid":null,"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":[]}