Research ArticleStroke

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

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Science Translational Medicine  07 Apr 2021:
Vol. 13, Issue 588, eabb1498
DOI: 10.1126/scitranslmed.abb1498

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Creating an effective duo

The drug nerinetide exerts neuroprotective effects in stroke by interfering with the postsynaptic density protein PSD-95. However, in patients, nerinetide lost the therapeutic effects when administered with (or after) the tissue plasminogen activator alteplase. Here, Mayor-Nunez et al. investigated the interaction between nerinetide and alteplase in rodents and showed that plasmin, activated by alteplase, cleaved nerinetide. Administering nerinetide 30 min or more before alteplase avoided the cleavage and restored the therapeutic effect of nerinetide. Moreover, the authors developed a protease-insensitive nerinetide by changing the enantiomeric form of cleavage-sensitive amino acids. The results identified two feasible strategies that might improve the efficacy of nerinetide in combination with tissue plasminogen activators in patients after stroke.


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.

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