{"doi":"10.1021/jacs.3c06703","title":"Hormone Analogues with Unique Signaling Profiles from Replacement of α-Residue Triads with β/γ Diads","abstract":"We have applied an underexplored backbone modification strategy to generate new analogues of peptides that activate two clinically important class B1 G protein-coupled receptors (GPCRs). Most peptide modification strategies involve changing side chains or, less commonly, changing the configuration at side chain-bearing carbons (i.e., l residues replaced by d residues). In contrast, backbone modifications alter the number of backbone atoms and the identities of backbone atoms relative to a poly-α-amino acid backbone. Starting from the peptide agonists PTH(1-34) (the first 34 residues of the parathyroid hormone, used clinically as the drug teriparatide) and glucagon-like peptide-1 (7-36) (GLP-1(7-36)), we replaced native α-residue triads with a diad composed of a β-amino acid residue and a γ-amino acid residue. The β/γ diad retains the number of backbone atoms in the ααα triad. Because the β and γ residue each bear a single side chain, we implemented ααα→βγ replacements at sites that contained a Gly residue (i.e., at α-residue triads that presented only two side chains). All seven of the α/β/γ-peptides derived from PTH(1-34) or GLP-1(7-36) bind to the cognate receptor (the PTHR1 or the GLP-1R), but they vary considerably in their activity profiles. Outcomes include functional mimicry of the all-α agonist, receptor-selective agonist activity, biased agonism, or strong binding with weak activation, which could lead to antagonist development. Collectively, these findings demonstrate that ααα→βγ replacements, which are easily implemented via solid-phase synthesis, can generate peptide hormone analogues that display unique and potentially useful signaling behavior.","journal":"Journal of the American Chemical Society","year":2023,"id":352996,"datarank":0.32958368660043297,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.0,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9531,"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":920637,"name":"Tae Wook Kim","orcid":"0000-0002-3478-6422","position":1,"is_corresponding":false},{"id":1098860,"name":"Lauren My-Linh Tran","orcid":"0000-0001-7554-676X","position":2,"is_corresponding":false},{"id":294605,"name":"Samuel H. Gellman","orcid":"0000-0001-5617-0058","position":3,"is_corresponding":false},{"id":726244,"name":"Ruslan Gibadullin","orcid":"0000-0001-8439-0218","position":0,"is_corresponding":true}],"reference_count":85,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:12:54.209378Z","pmid":"37697685","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":[]}