{"doi":"10.1128/aac.00562-24","title":"Design of novel and highly selective SARS-CoV-2 main protease inhibitors","abstract":"ABSTRACT We have synthesized a novel and highly selective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease peptide mimetic inhibitor mimicking the replicase 1ab recognition sequence -Val-Leu-Gln- and utilizing a cysteine selective acyloxymethyl ketone as the electrophilic warhead to target the active site Cys145. Utilizing a constrained cyclic peptide that locks the conformation between the P3 (Val) and P2 (Leu) residues, we identified a highly selective inhibitor that fills the P2 pocket occupied by the leucine residue sidechain of PF-00835231 and the dimethyl-3-azabicyclo-hexane motif in nirmatrelvir (PF-07321332). This strategy resulted in potent and highly selective Mpro inhibitors without inhibiting essential host cathepsin cysteine or serine proteases. The lead prototype compound 1 (MPro IC 50 = 230 ± 18 nM) also inhibits the replication of multiple SARS-CoV-2 variants in vitro , including SARS-CoV-2 variants of concern, and can synergize at lower concentrations with the viral RNA polymerase inhibitor, remdesivir, to inhibit replication. It also reduces SARS-CoV-2 replication in SARS-CoV-2 Omicron-infected Syrian golden hamsters without obvious toxicities, demonstrating in vivo efficacy. This novel lead structure provides the basis for optimization of improved agents targeting evolving SARS-CoV-2 drug resistance that can selectively act on Mpro versus host proteases and are less likely to have off-target effects due to non-specific targeting. Developing inhibitors against the active site of the main protease (Mpro), which is highly conserved across coronaviruses, is expected to impart a higher genetic barrier to evolving SARS-CoV-2 drug resistance. Drugs that selectively inhibit the viral Mpro are less likely to have off-target effects warranting efforts to improve this therapy.","journal":"Antimicrobial Agents and Chemotherapy","year":2024,"id":445447,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9635,"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":301195,"name":"Ian Tietjen","orcid":"0000-0002-8991-6490","position":1,"is_corresponding":false},{"id":846109,"name":"Nitesh Kumar Nandwana","orcid":"0000-0003-1203-7006","position":2,"is_corresponding":false},{"id":348572,"name":"Joel Cassel","orcid":"0000-0001-8465-8739","position":3,"is_corresponding":false},{"id":378068,"name":"Troy E. Messick","orcid":"0000-0001-7914-1524","position":4,"is_corresponding":false},{"id":1261844,"name":"Emery T. Register","orcid":null,"position":5,"is_corresponding":false},{"id":626660,"name":"Frederick Keeney","orcid":null,"position":6,"is_corresponding":false},{"id":432435,"name":"Rajesh Rajaiah","orcid":"0000-0001-6506-891X","position":7,"is_corresponding":false},{"id":672520,"name":"Atul Kumar","orcid":"0000-0002-8217-8181","position":8,"is_corresponding":false},{"id":297034,"name":"Kabita Pandey","orcid":null,"position":9,"is_corresponding":false},{"id":296005,"name":"Arpan Acharya","orcid":"0000-0003-2721-1062","position":10,"is_corresponding":false},{"id":69434,"name":"Siddappa N. Byrareddy","orcid":"0000-0002-6889-4640","position":11,"is_corresponding":false},{"id":251284,"name":"Luis J. Montaner","orcid":"0000-0001-5799-6759","position":12,"is_corresponding":false},{"id":348575,"name":"Joseph M. Salvino","orcid":"0000-0002-2184-5980","position":13,"is_corresponding":false},{"id":492302,"name":"Adi Narayana Reddy Poli","orcid":"0000-0001-6288-9229","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-19T02:01:42.089235Z","pmid":"39225484","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":[]}