{"doi":"10.1101/2024.11.10.622803","title":"Programmable protein degraders enable selective knockdown of pathogenic β-catenin subpopulations <i>in vitro</i> and <i>in vivo</i>","abstract":"ABSTRACT Aberrant activation of Wnt signaling results in unregulated accumulation of cytosolic β-catenin, which subsequently enters the nucleus and promotes transcription of genes that contribute to cellular proliferation and malignancy. Here, we sought to eliminate pathogenic β-catenin from the cytosol using designer ubiquibodies (uAbs), chimeric proteins composed of an E3 ubiquitin ligase and a target-binding domain that redirect intracellular proteins to the proteasome for degradation. To accelerate uAb development, we leveraged a protein language model (pLM)-driven algorithm called SaLT&amp;PepPr to computationally design “guide” peptides with affinity for β-catenin, which were subsequently fused to the catalytic domain of a human E3 called C-terminus of Hsp70-interacting protein (CHIP). Expression of the resulting peptide-guided uAbs in colorectal cancer cells led to the identification of several designs that significantly reduced the abnormally stable pool of free β-catenin in the cytosol and nucleus while preserving the normal membrane-associated subpopulation. This selective knockdown of pathogenic β-catenin suppressed Wnt/β-catenin signaling and impaired tumor cell survival and proliferation. Furthermore, one of the best degraders selectively decreased cytosolic but not membrane-associated β-catenin levels in livers of BALB/c mice following delivery as a lipid nanoparticle (LNP)-encapsulated mRNA. Collectively, these findings reveal the unique ability of uAbs to selectively eradicate abnormal proteins in vitro and in vivo and open the door to peptide-programmable biologic modulators of other disease-causing proteins.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":486435,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9513,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1224808,"name":"Azmain Alamgir","orcid":"0000-0002-8198-0148","position":1,"is_corresponding":false},{"id":1000517,"name":"Cara M. Robertus","orcid":"0000-0002-6230-1509","position":2,"is_corresponding":false},{"id":1330654,"name":"Darianna Colina","orcid":null,"position":3,"is_corresponding":false},{"id":712421,"name":"Connor Monticello","orcid":null,"position":4,"is_corresponding":false},{"id":613340,"name":"Thomas Connor Donahue","orcid":null,"position":5,"is_corresponding":false},{"id":1027981,"name":"Lauren Hong","orcid":"0000-0002-1675-4806","position":6,"is_corresponding":false},{"id":1160946,"name":"Sophia Vincoff","orcid":null,"position":7,"is_corresponding":false},{"id":1160951,"name":"Shrey Goel","orcid":null,"position":8,"is_corresponding":false},{"id":186465,"name":"Peter Fekkes","orcid":null,"position":9,"is_corresponding":false},{"id":1330221,"name":"Luiz Miguel Camargo","orcid":"0000-0002-0688-3700","position":10,"is_corresponding":false},{"id":1330222,"name":"Kieu Lam","orcid":"0000-0002-1965-5491","position":11,"is_corresponding":false},{"id":903977,"name":"James Heyes","orcid":"0000-0001-9499-2028","position":12,"is_corresponding":false},{"id":339742,"name":"David Putnam","orcid":"0000-0002-0794-4915","position":13,"is_corresponding":false},{"id":395046,"name":"Christopher A. Alabi","orcid":"0000-0003-2654-018X","position":14,"is_corresponding":false},{"id":263226,"name":"Pranam Chatterjee","orcid":"0000-0003-3957-8478","position":15,"is_corresponding":false},{"id":325467,"name":"Matthew P. DeLisa","orcid":"0000-0003-3226-1566","position":16,"is_corresponding":false},{"id":711723,"name":"Tianzheng Ye","orcid":"0000-0001-6678-7115","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:08:01.404471Z","pmid":"39605463","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":[]}