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Tat-NR2B9c, also known as Tat-NR2Bct, NA-1, or nerinetide, is a 20-amino-acid peptide designed to inhibit postsynaptic density protein-95 (PSD-95). It achieves this by mimicking the C-terminal sequence of the NR2B subunit of the NMDA receptor, thereby disrupting critical protein-protein interactions involved in excitotoxic signaling.
Mechanism of Action
Tat-NR2B9c specifically targets the PDZ domains of PSD-95, with high affinity for PDZ domain 2 (EC₅₀ ≈ 6.7 nM) and lower affinity for PDZ domain 1 (EC₅₀ ≈ 670 nM) . By binding to these domains, the peptide disrupts the interaction between PSD-95 and NMDA receptor subunits NR2A and NR2B, with inhibitory concentrations (IC₅₀) of approximately 0.5 μM and 8 μM, respectively . Additionally, Tat-NR2B9c interferes with the association between PSD-95 and neuronal nitric oxide synthase (nNOS), exhibiting an IC₅₀ of about 200 nM.
Neuroprotective Properties
By disrupting these interactions, Tat-NR2B9c attenuates downstream neurotoxic signaling pathways, including the production of reactive oxygen species and activation of pro-death kinases like p38 MAPK. This results in neuroprotection in various models of neuronal injury. For instance, in rodent models of ischemic stroke, administration of Tat-NR2B9c reduced infarct volumes and improved neurological outcomes . Similarly, in vitro studies have demonstrated its efficacy in protecting neurons from NMDA-induced excitotoxicity.
Clinical and Research Applications
Tat-NR2B9c has advanced to clinical trials, notably the ENACT and ESCAPE-NA1 trials, evaluating its potential in reducing ischemic brain damage during endovascular procedures . While promising results have been observed in primate models and early-phase human trials, efficacy in murine models has been inconsistent, potentially due to species-specific differences in pharmacodynamics and dosing requirements.
Beyond stroke, Tat-NR2B9c has shown potential in mitigating neuropathic pain by disrupting NR2B/PSD-95 interactions in the spinal cord, leading to reduced pain hypersensitivity.
Considerations and Limitations
While Tat-NR2B9c exhibits significant neuroprotective properties, its efficacy can be influenced by factors such as timing of administration, dosage, and species-specific responses. For example, higher doses were required to achieve neuroprotection in mice compared to rats . Additionally, modifications to the peptide, such as substituting the Tat sequence with D-Tat, have been shown to reduce its neuroprotective efficacy, likely due to decreased cellular uptake.
Tat-NR2B9c is a potent PSD-95 inhibitor with demonstrated neuroprotective effects in various models of neuronal injury. Its ability to disrupt critical protein-protein interactions involved in excitotoxic signaling makes it a promising therapeutic candidate for conditions such as stroke and neuropathic pain.
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