{"doi":"10.1126/scitranslmed.abb1498","title":"Plasmin-resistant PSD-95 inhibitors resolve effect-modifying drug-drug interactions between alteplase and nerinetide in acute stroke","abstract":"Neuroprotection for acute ischemic stroke is achievable with the eicosapeptide nerinetide, an inhibitor of the protein-protein interactions of the synaptic scaffolding protein PSD-95. However, nerinetide is subject to proteolytic cleavage if administered after alteplase, a standard-of-care thrombolytic agent that nullifies nerinetide's beneficial effects. Here, we showed, on the basis of pharmacokinetic data consistent between rats, primates, and humans, that in a rat model of embolic middle cerebral artery occlusion (eMCAO), nerinetide maintained its effectiveness when administered before alteplase. Because of its short plasma half-life, it can be followed by alteplase within minutes without reducing its neuroprotective effectiveness. In addition, the problem of protease sensitivity is solved by substituting cleavage-prone amino acids from their l- to their d-enantiomeric form. Treatment of rats subjected to eMCAO with such an agent, termed d-Tat-l-2B9c, eliminated protease sensitivity and maintained neuroprotective effectiveness. Our data suggest that both the clinical-stage PSD-95 inhibitor nerinetide and protease-resistant agents such as d-Tat-l-2B9c may be practically integrated into existing stroke care workflows and standards of care.","journal":"Science Translational Medicine","year":2021,"id":154835,"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":61,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9557,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":656269,"name":"Zhanxin Ji","orcid":null,"position":1,"is_corresponding":false},{"id":655659,"name":"Xiujun Sun","orcid":"0000-0001-5925-7044","position":2,"is_corresponding":false},{"id":656270,"name":"Lucy Teves","orcid":null,"position":3,"is_corresponding":false},{"id":656271,"name":"J. David Garman","orcid":null,"position":4,"is_corresponding":false},{"id":425653,"name":"Michael Tymianski","orcid":"0000-0002-6311-9565","position":5,"is_corresponding":false},{"id":655658,"name":"Diana Mayor","orcid":"0000-0001-7598-1358","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-18T23:43:54.469024Z","pmid":"33827973","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":[]}