{"doi":"10.1101/2023.10.03.560749","title":"Optimizing Phosphopeptide Structures That Target 14-3-3ε in Cutaneous Squamous Cell Carcinoma","abstract":"ABSTRACT 14-3-3ε is involved in various types of malignancies by increasing cell proliferation, promoting cell invasion or inhibiting apoptosis. In cutaneous squamous cell carcinoma (cSCC), 14-3-3ε is over expressed and mislocalized from the nucleus to the cytoplasm where it interacts with the cell division cycle 25 A (CDC25A) and suppresses apoptosis. Hence inhibition of the 14-3-3ε - CDC25A interaction is an attractive target for promoting apoptosis in cSCC. In this work, we optimized the structure of our previously designed inhibitor of 14-3-3ε – CDC25A interaction, pT, a phosphopeptide fragment corresponding to one of the two binding regions of CDC25A to 14-3-3ε. Starting from pT, we developed peptide analogs that bind 14-3-3ε with nanomolar affinities. Peptide analogs were designed by shortening the pT peptide, and introducing modifications at position 510 of the pT(502-510) analog. Both molecular dynamics (MD) simulations and biophysical methods were used to determine peptides binding to 14-3-3ε. Shortening the pT peptide from 14 to 9 amino acid residues resulted in a peptide (pT(502-510)) that binds 14-3-3ε with a K D value of 45.2 nM. Gly to Phe substitution in position 510 of pT(502-510) led to further improvement in affinity (K D : 22.0 nM) of the peptide for 14-3-3ε. Our results suggest that the designed peptide analogs are potential candidates for inhibiting 14-3-3ε -CDC25A interactions in cSCC cells; thus, inducing their apoptosis.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":412243,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9485,"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":397938,"name":"Sibaprasad Maity","orcid":"0000-0001-8493-0210","position":1,"is_corresponding":false},{"id":526668,"name":"Lynne M. Dieckman","orcid":"0000-0002-1532-0897","position":2,"is_corresponding":false},{"id":369894,"name":"Laura A. Hansen","orcid":"0000-0003-3436-8412","position":3,"is_corresponding":false},{"id":369893,"name":"Sándor Lovas","orcid":"0000-0002-5089-5186","position":4,"is_corresponding":false},{"id":1193456,"name":"Seraphine Kamayirese","orcid":null,"position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:21:50.261851Z","pmid":"37873379","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":[]}