{"doi":"10.1101/2023.01.17.524469","title":"A Systematic Survey of Reversibly Covalent Dipeptidyl Inhibitors of the SARS-CoV-2 Main Protease","abstract":"Abstract SARS-CoV-2 is the coronavirus pathogen of the currently prevailing COVID-19 pandemic. It relies on its main protease (M Pro ) for replication and pathogenesis. M Pro is a demonstrated target for the development of antivirals for SARS-CoV-2. Past studies have systematically explored tripeptidyl inhibitors such as nirmatrelvir as M Pro inhibitors. However, dipeptidyl inhibitors especially those with a spiro residue at their P2 position have not been systematically investigated. In this work, we synthesized about 30 reversibly covalent dipeptidyl M Pro inhibitors and characterized them on in vitro enzymatic inhibition potency, structures of their complexes with M Pro , cellular M Pro inhibition potency, antiviral potency, cytotoxicity, and in vitro metabolic stability. Our results indicated that M Pro has a flexible S2 pocket that accommodates dipeptidyl inhibitors with a large P2 residue and revealed that dipeptidyl inhibitors with a large P2 spiro residue such as ( S )-2-azaspiro[4,4]nonane-3-carboxylate and ( S )-2-azaspiro[4,5]decane-3-carboxylate have optimal characteristics. One compound MPI60 containing a P2 ( S )-2-azaspiro[4,4]nonane-3-carboxylate displayed high antiviral potency, low cellular cytotoxicity, and high in vitro metabolic stability and can be potentially advanced to further preclinical tests.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":392876,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9588,"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":1048462,"name":"Sandeep Atla","orcid":"0000-0001-9960-5429","position":1,"is_corresponding":false},{"id":419670,"name":"Namir Shaabani","orcid":"0000-0003-3548-5899","position":2,"is_corresponding":false},{"id":1048463,"name":"Veerabhadra R. Vulupala","orcid":"0000-0002-6224-5674","position":3,"is_corresponding":false},{"id":264693,"name":"Kai S. Yang","orcid":"0000-0002-1890-4169","position":4,"is_corresponding":false},{"id":265652,"name":"Yugendar R. Alugubelli","orcid":null,"position":5,"is_corresponding":false},{"id":815495,"name":"Kaustav Khatua","orcid":"0000-0002-2497-3187","position":6,"is_corresponding":false},{"id":456395,"name":"Peng‐Hsun Chase Chen","orcid":"0000-0001-9822-6398","position":7,"is_corresponding":false},{"id":417716,"name":"Jing Xiao","orcid":"0000-0002-6525-252X","position":8,"is_corresponding":false},{"id":264699,"name":"Lauren R. Blankenship","orcid":"0000-0002-1714-4399","position":9,"is_corresponding":false},{"id":264694,"name":"R. Xinyu","orcid":"0000-0002-4798-6095","position":10,"is_corresponding":false},{"id":264697,"name":"Erol C. Vatansever","orcid":"0000-0002-8392-5791","position":11,"is_corresponding":false},{"id":553387,"name":"Chia-Chuan Cho","orcid":null,"position":12,"is_corresponding":false},{"id":264695,"name":"Yuying Ma","orcid":"0000-0003-4276-1214","position":13,"is_corresponding":false},{"id":815496,"name":"Robert D. Allen","orcid":"0000-0001-9950-103X","position":14,"is_corresponding":false},{"id":815906,"name":"Henry Ji","orcid":null,"position":15,"is_corresponding":false},{"id":264703,"name":"Shiqing Xu","orcid":"0000-0001-6260-9290","position":16,"is_corresponding":false},{"id":264704,"name":"Wenshe Ray Liu","orcid":"0000-0002-7078-6534","position":17,"is_corresponding":false},{"id":264698,"name":"Zhi Geng","orcid":"0000-0002-5764-6190","position":0,"is_corresponding":true}],"reference_count":20,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:19:01.355412Z","pmid":"36711580","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":[]}