{"doi":"10.1021/acsptsci.2c00049","title":"Allosteric Binders of ACE2 Are Promising Anti-SARS-CoV-2 Agents","abstract":"The COVID-19 pandemic has had enormous health, economic, and social consequences. Vaccines have been successful in reducing rates of infection and hospitalization, but there is still a need for acute treatment of the disease. We investigate whether compounds that bind the human angiotensin-converting enzyme 2 (ACE2) protein can decrease SARS-CoV-2 replication without impacting ACE2’s natural enzymatic function. Initial screening of a diversity library resulted in hit compounds active in an ACE2-binding assay, which showed little inhibition of ACE2 enzymatic activity (116 actives, success rate ∼4%), suggesting they were allosteric binders. Subsequent application of in silico techniques boosted success rates to ∼14% and resulted in 73 novel confirmed ACE2 binders with Kd values as low as 6 nM. A subsequent SARS-CoV-2 assay revealed that five of these compounds inhibit the viral life cycle in human cells. Further effort is required to completely elucidate the antiviral mechanism of these ACE2-binders, but they present a valuable starting point for both the development of acute treatments for COVID-19 and research into the host-directed therapy.","journal":"ACS Pharmacology & Translational Science","year":2022,"id":252685,"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":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9604,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":636400,"name":"Sankalp Jain","orcid":"0000-0002-9370-9611","position":1,"is_corresponding":false},{"id":292561,"name":"Cleber C. Melo‐Filho","orcid":"0000-0003-0056-6971","position":2,"is_corresponding":false},{"id":323436,"name":"Zoe L. Sessions","orcid":"0000-0002-5850-467X","position":3,"is_corresponding":false},{"id":268255,"name":"Tesia Bobrowski","orcid":"0000-0002-6177-374X","position":4,"is_corresponding":false},{"id":732413,"name":"Jun Choe","orcid":"0000-0002-3389-5969","position":5,"is_corresponding":false},{"id":897883,"name":"Johnny Zheng","orcid":null,"position":6,"is_corresponding":false},{"id":268257,"name":"Richard T. Eastman","orcid":"0000-0003-3580-380X","position":7,"is_corresponding":false},{"id":365516,"name":"Daniel C. Talley","orcid":null,"position":8,"is_corresponding":false},{"id":268294,"name":"Ganesha Rai","orcid":"0000-0001-9763-9641","position":9,"is_corresponding":false},{"id":228423,"name":"Anton Simeonov","orcid":"0000-0002-4523-9977","position":10,"is_corresponding":false},{"id":108077,"name":"Alexander Tropsha","orcid":"0000-0003-3802-8896","position":11,"is_corresponding":false},{"id":12435,"name":"Eugene Muratov","orcid":"0000-0003-4616-7036","position":12,"is_corresponding":false},{"id":228430,"name":"Bolormaa Baljinnyam","orcid":"0000-0001-9548-4965","position":13,"is_corresponding":false},{"id":12541,"name":"Alexey Zakharov","orcid":"0000-0003-2466-1711","position":14,"is_corresponding":false},{"id":897248,"name":"Joshua E. Hochuli","orcid":"0000-0003-4487-3228","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T00:24:50.819822Z","pmid":"35821746","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":[]}