Plasmin-resistant PSD-95 inhibitors resolve effect-modifying drug-drug interactions between alteplase and nerinetide in acute stroke.

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  • Additional Information
    • Source:
      Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : American Association for the Advancement of Science
    • Subject Terms:
      Antifibrinolytic Agents*/pharmacology ; Brain Ischemia* ; Stroke*/drug therapy; Disks Large Homolog 4 Protein/*antagonists & inhibitors ; Fibrinolysin/*pharmacology ; Tissue Plasminogen Activator/*pharmacology; Animals ; Drug Interactions ; Rats
    • 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.
      (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
    • Grant Information:
      U01 NS087876 United States NS NINDS NIH HHS
    • Accession Number:
      0 (Antifibrinolytic Agents)
      0 (Disks Large Homolog 4 Protein)
      0 (Dlg4 protein, rat)
      EC 3.4.21.68 (Tissue Plasminogen Activator)
      EC 3.4.21.7 (Fibrinolysin)
    • Publication Date:
      Date Created: 20210408 Date Completed: 20210712 Latest Revision: 20220531
    • Publication Date:
      20221213
    • Accession Number:
      10.1126/scitranslmed.abb1498
    • Accession Number:
      33827973