{"doi":"10.1021/acschembio.2c00403","title":"Serum-Stable and Selective Backbone-N-Methylated Cyclic Peptides That Inhibit Prokaryotic Glycolytic Mutases","abstract":"N-Methylated amino acids (N-MeAAs) are privileged residues of naturally occurring peptides critical to bioactivity. However, de novo discovery from ribosome display is limited by poor incorporation of N-methylated amino acids into the nascent peptide chain attributed to a poor EF-Tu affinity for the N-methyl-aminoacyl-tRNA. By reconfiguring the tRNA’s T-stem region to compensate and tune the EF-Tu affinity, we conducted Random nonstandard Peptides Integrated Discovery (RaPID) display of a macrocyclic peptide (MCP) library containing six different N-MeAAs. We have here devised a “pool-and-split” enrichment strategy using the RaPID display and identified N-methylated MCPs against three species of prokaryotic metal-ion-dependent phosphoglycerate mutases. The enriched MCPs reached 57% N-methylation with up to three consecutively incorporated N-MeAAs, rivaling natural products. Potent nanomolar inhibitors ranging in ortholog selectivity, strongly mediated by N-methylation, were identified. Co-crystal structures reveal an architecturally related Ce-2 Ipglycermide active-site metal-ion-coordinating Cys lariat MCP, functionally dependent on two cis N-MeAAs with broadened iPGM species selectivity over the original nematode-selective MCPs. Furthermore, the isolation of a novel metal-ion-independent Staphylococcus aureus iPGM inhibitor utilizing a phosphoglycerate mimetic mechanism illustrates the diversity of possible chemotypes encoded by the N-MeAA MCP library.","journal":"ACS Chemical Biology","year":2022,"id":247837,"datarank":0.5244761342199721,"base_score":3.4965075614664802,"endowment":3.4965075614664802,"self_citation_contribution":0.5244761342199721,"citation_network_contribution":0.0,"self_endowment_contribution":0.5244761342199721,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":32,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9477,"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":409319,"name":"Patricia Dranchak","orcid":"0000-0002-1349-4885","position":1,"is_corresponding":false},{"id":442778,"name":"L. Liu","orcid":null,"position":2,"is_corresponding":false},{"id":764646,"name":"Mahesh Aitha","orcid":"0000-0003-0377-4792","position":3,"is_corresponding":false},{"id":764647,"name":"Bryan Queme","orcid":"0000-0003-1509-9982","position":4,"is_corresponding":false},{"id":886104,"name":"Hiroyuki Kimura","orcid":"0000-0002-5297-3264","position":5,"is_corresponding":false},{"id":886105,"name":"Takayuki Katoh","orcid":"0000-0001-6550-6203","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":409320,"name":"James Inglese","orcid":"0000-0002-7332-5717","position":9,"is_corresponding":false},{"id":426660,"name":"Hiroaki Suga","orcid":"0000-0002-5298-9186","position":10,"is_corresponding":false},{"id":886103,"name":"Renier H. P. van Neer","orcid":"0000-0002-9131-3824","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:23:57.824223Z","pmid":"35904259","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":[]}