PMS-001 is a brand-new polypeptide drug for treating stroke, drug addiction, severe depression, and Alzheimer's disease.Its effective ingredient is interfering peptides.

Under normal circumstances, the endocytosis of AMPA receptors in the postsynaptic membrane is balanced by the membrane insertion. This ensures a stable number of receptors on the postsynaptic membrane, and thereby maintaining the normal transmission of nerve signals. Under some pathological conditions, the amount of AMPA receptors endocytosis continuously outnumbers that of the membrane insertion due to the over-activation of excitatory glutamate receptors. Which results in the reduction of AMPA receptors in the postsynaptic membrane, thus triggering long-term depression (LTD) of synaptic transmission and eventually leads to nerve cell death.

At present, it has been confirmed that the occurrence of numerous neurological diseases (such as drug addiction, Alzheimer's disease, cerebral stroke, major depression, etc.) is strongly associated with this process. Further research has revealed that this process is affected by a specific amino acid sequence containing multiple tyrosines in the C-terminal segment of the receptor in the AMPA receptor GluA2 subtype cells (A867-G877). The amino acid sequence further activates guanosine triphosphatase Arf6 through the interaction with Brag2, a synaptic protein. Guanosine triphosphatase Arf6 not only helps actin remodeling of the membrane, but also directly plays a significant role in the formation of synaptic vesicles mediated by grid protein, thus leading to the endocytosis of postsynaptic membrane AMPA receptor. During the entire regulatory process, the combination of AMPA receptor C-terminal and Brag2 synaptic protein plays a vital role. By interfering with their interaction, the hyper-endocytosis of postsynaptic membrane receptor can be greatly reduced, thus undermining the formation of LTD. Based on this mechanism, we have designed a mimetic peptide with reference to this sequence and added a Tat sequence to help it pass through the blood-brain barrier. The PMS-001 polypeptide can treat related neurological diseases by competitively bind to Brag2 synaptic protein which inhibits the activation of Arf6 and reduces the hyper-endocytosis of AMPA receptor caused by synaptic vesicles.

Links for related articles:

Drug addiction:https://science.sciencemag.org/content/310/5752/1340

Alzheimer's disease:https://www.jci.org/articles/view/77888

Cerebral stroke: https://www.jbc.org/content/279/40/41267.full.pdf?sid=81430910-6051-4d56-b511-a5930f5b31a3