{"doi":"10.1038/nchembio.664","title":"On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds","abstract":null,"journal":"Nature Chemical Biology","year":2011,"id":675567,"datarank":12.356749637057531,"base_score":5.973809611869261,"endowment":5.973809611869261,"self_citation_contribution":0.8960714417803893,"citation_network_contribution":11.460678195277142,"self_endowment_contribution":0.8960714417803893,"citer_contribution":11.460678195277142,"corpus_percentile":null,"corpus_rank":null,"citation_count":392,"citer_count":200,"citers_with_citation_signal":200,"citers_with_endowment":200,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1765132,"name":"Chad M Renzelman","orcid":null,"position":1,"is_corresponding":false},{"id":1765134,"name":"Arthur C Rand","orcid":null,"position":2,"is_corresponding":false},{"id":1765136,"name":"Taha Rezai","orcid":null,"position":3,"is_corresponding":false},{"id":1765138,"name":"Cayla M McEwen","orcid":null,"position":4,"is_corresponding":false},{"id":1765139,"name":"Vladimir M Gelev","orcid":null,"position":5,"is_corresponding":false},{"id":1765141,"name":"Rushia A Turner","orcid":null,"position":6,"is_corresponding":false},{"id":1649905,"name":"Roger G Linington","orcid":null,"position":7,"is_corresponding":false},{"id":1765144,"name":"Siegfried S F Leung","orcid":null,"position":8,"is_corresponding":false},{"id":1765145,"name":"Amit S Kalgutkar","orcid":null,"position":9,"is_corresponding":false},{"id":1765146,"name":"Jonathan N Bauman","orcid":null,"position":10,"is_corresponding":false},{"id":1765148,"name":"Yizhong Zhang","orcid":null,"position":11,"is_corresponding":false},{"id":1701659,"name":"Spiros Liras","orcid":null,"position":12,"is_corresponding":false},{"id":1079436,"name":"David A Price","orcid":null,"position":13,"is_corresponding":false},{"id":1765150,"name":"Alan M Mathiowetz","orcid":null,"position":14,"is_corresponding":false},{"id":1642213,"name":"Matthew P Jacobson","orcid":null,"position":15,"is_corresponding":false},{"id":1707575,"name":"R Scott Lokey","orcid":null,"position":16,"is_corresponding":false},{"id":1765131,"name":"Tina R White","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds","abstract":"Backbone N-methylation is common among peptide natural products and has a substantial impact on both the physical properties and the conformational states of cyclic peptides. However, the specific impact of N-methylation on passive membrane diffusion in cyclic peptides has not been investigated systematically. Here we report a method for the selective, on-resin N-methylation of cyclic peptides to generate compounds with drug-like membrane permeability and oral bioavailability. The selectivity and degree of N-methylation of the cyclic peptide was dependent on backbone stereochemistry, suggesting that conformation dictates the regiochemistry of the N-methylation reaction. The permeabilities of the N-methyl variants were corroborated by computational studies on a 1,024-member virtual library of N-methyl cyclic peptides. One of the most permeable compounds, a cyclic hexapeptide (molecular mass = 755 Da) with three N-methyl groups, showed an oral bioavailability of 28% in rat.","is_dataset_classified":null,"base_score":5.973809611869261,"endowment":5.973809611869261,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"21946276","pmcid":"PMC3210067","openalex_id":"https://openalex.org/W2050991123","authors":[],"funders":[{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM084530","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"GM084530-06","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R01 GM086602","title":null},{"funder_name":"NIGMS NIH HHS","grant_id":"R01-GM086602","title":null},{"funder_name":"National Institutes of Health","grant_id":"5R01GM086602-03","title":"Understanding, Predicting, and Engineering Membrane Permeability"},{"funder_name":"National Institutes of Health","grant_id":"2R01GM084530-06A2","title":"Synthesis and discovery of biologically active cell-permeable  cyclic peptides"}],"total_grants":6,"fwci":8.9962,"citation_percentile":0.9872463,"influential_citations":0,"citation_trend":[{"year":2012,"count":19},{"year":2013,"count":21},{"year":2014,"count":34},{"year":2015,"count":26},{"year":2016,"count":31},{"year":2017,"count":30},{"year":2018,"count":30},{"year":2019,"count":24},{"year":2020,"count":25},{"year":2021,"count":22},{"year":2022,"count":32},{"year":2023,"count":22},{"year":2024,"count":25},{"year":2025,"count":30},{"year":2026,"count":21}],"oa_status":"closed","license":"Springer TDM","oa_locations":[{"url":"http://www.nature.com/articles/nchembio.664.pdf","host_type":"publisher"},{"url":"http://www.nature.com/articles/nchembio.664","host_type":"publisher"},{"url":"https://doi.org/10.1038/nchembio.664","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/21946276","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/3210067","host_type":"repository"},{"url":"https://escholarship.org/uc/item/5wh884tn","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC3210067","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC3210067?pdf=render","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/pmc3210067?pdf=render","host_type":""},{"url":"http://dx.doi.org/10.1038/nchembio.664","host_type":""},{"url":"https://dx.doi.org/10.1038/nchembio.664","host_type":""},{"url":"https://doi.org/https://doi.org/10.1038/nchembio.664","host_type":""}],"fields_of_study":["Chemical Synthesis and Analysis","Cancer-related gene regulation","Click Chemistry and Applications","0301 basic medicine","01 natural sciences","03 medical and health sciences","0104 chemical sciences"],"mesh_terms":["Animals","Biological Availability","Chemistry, Pharmaceutical","Computer Simulation","Male","Methylation","Peptides, Cyclic","Structure-Activity Relationship","Molecular Structure","Combinatorial Chemistry Techniques","Rats","Drug Discovery"],"keywords":["Cyclic peptide","Chemistry","Methylation","Peptide","Intramolecular force","Membrane permeability","Membrane","Bioavailability","Regioselectivity","Hydrogen bond","Stereochemistry","Biochemistry","Molecule","Organic chemistry","Bioinformatics","Gene","Biology","Male","Biochemistry & Molecular Biology","Chemistry, Pharmaceutical","Biological Availability","Peptides, Cyclic","Article","Inorganic Chemistry","Medicinal and Biomolecular Chemistry","Structure-Activity Relationship","Drug Discovery","Animals","Combinatorial Chemistry Techniques","Computer Simulation","Cyclic","Molecular Structure","Rats","Biochemistry and cell biology","Chemical Sciences","Pharmaceutical","Peptides"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Clean water and sanitation"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-17T01:22:52.115316Z","pmid":null,"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":[]}