Plasmin-resistant PSD-95 inhibitors resolve effect-modifying drug-drug interactions between alteplase and nerinetide in acute stroke.
Diana MayorZhanxin JiXiujun SunLucy TevesJ David GarmanMichael TymianskiPublished in: Science translational medicine (2021)
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.
Keyphrases
- acute ischemic stroke
- middle cerebral artery
- healthcare
- randomized controlled trial
- palliative care
- systematic review
- cerebral ischemia
- quality improvement
- amino acid
- electronic health record
- pain management
- big data
- dna binding
- brain injury
- adverse drug
- emergency department
- atrial fibrillation
- blood brain barrier
- pulmonary embolism
- subarachnoid hemorrhage
- protein protein
- deep learning
- capillary electrophoresis