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.

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