{"doi":"10.1021/jacs.3c06694","title":"Inhibition of Hypoxia-Inducible Transcription Factor (HIF-1α) Signaling with Sulfonyl-γ-AApeptide Helices","abstract":"The development of inhibitors that selectively block protein-protein interactions (PPIs) is crucial for chemical biology, medicinal chemistry, and biomedical sciences. Herein, we reported the design, synthesis, and investigation of sulfonyl-γ-AApeptide as an alternative strategy of canonical peptide-based inhibitors to disrupt hypoxia-inducible factor 1α (HIF-1α) and p300 PPI by mimicking the helical domain of HIF-1α involved in the binding to p300. The designed molecules recognized the p300 protein with high affinity and potently inhibited the hypoxia-inducible signaling pathway. Gene expression profiling supported the idea that the lead molecules selectively inhibited hypoxia-inducible genes involved in the signaling cascade. Our studies also demonstrated that both helical faces consisting of either chiral side chains or achiral sulfonyl side chains of sulfonyl-γ-AApeptides could be adopted for mimicry of the α-helix engaging in PPIs. Furthermore, these sulfonyl-γ-AApeptides were cell-permeable and exhibited favorable stability and pharmacokinetic profiles. Our results could inspire the design of helical sulfonyl-γ-AApeptides as a general strategy to mimic the protein helical domain and modulate many other PPIs.","journal":"Journal of the American Chemical Society","year":2023,"id":336537,"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":0.9525,"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":1067348,"name":"Sami Abdulkadir","orcid":null,"position":1,"is_corresponding":false},{"id":1066989,"name":"Xue Zhao","orcid":"0000-0001-9281-7680","position":2,"is_corresponding":false},{"id":300808,"name":"Peng Sang","orcid":"0000-0002-8336-4533","position":3,"is_corresponding":false},{"id":622307,"name":"Αναστασία Τοματσίδου","orcid":null,"position":4,"is_corresponding":false},{"id":107692,"name":"Xiujun Zhang","orcid":"0000-0001-8041-0592","position":5,"is_corresponding":false},{"id":107695,"name":"Yu Chen","orcid":"0000-0002-5115-3600","position":6,"is_corresponding":false},{"id":321206,"name":"Laurent Calcul","orcid":"0009-0001-4402-2813","position":7,"is_corresponding":false},{"id":653526,"name":"Xingmin Sun","orcid":"0000-0002-8900-9161","position":8,"is_corresponding":false},{"id":422132,"name":"Feng Cheng","orcid":"0000-0003-3619-8090","position":9,"is_corresponding":false},{"id":751112,"name":"Yong Hu","orcid":"0000-0002-5394-6743","position":10,"is_corresponding":false},{"id":300813,"name":"Jianfeng Cai","orcid":"0000-0003-3106-3306","position":11,"is_corresponding":false},{"id":1066988,"name":"Wei Jiang","orcid":"0009-0005-6766-5482","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-19T01:10:17.243221Z","pmid":"37665648","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":[]}