Structure‐based design of peptidomimetic inhibitors of PSD‐95 with improved affinity for the PDZ3 domain

Aberrant brain‐derived neurotrophic factor (BDNF) signaling has been proposed to contribute to the pathophysiology of depression and other neurological disorders such as Angelman syndrome. We have previously shown that targeting the tropomyosin receptor kinase B/postsynaptic density protein‐95 (PSD‐95) nexus in the BDNF signaling pathway by peptidomimetic inhibitors is a promising approach for therapeutic intervention. Here, we used structure‐based knowledge to develop a new Syn3 peptidomimetic compound series that fuses peptides derived from the PSD‐95‐binding protein SynGAP to our prototype compound CN2097. The new compounds target the PSD‐95 PDZ3 domain and adjoining αC helix to achieve bivalent binding that results in up to 7‐fold stronger affinity compared to CN2097. These compounds were designed to improve CN2097 specificity for the PSD‐95 PDZ3 domain, and structure–activity relationship studies were performed to improve their resistance to proteolysis. Aberrant brain‐derived neurotrophic factor signaling is associated with a range of neurological disorders. Targeting postsynaptic density protein‐95 (PSD‐95), a scaffolding protein in this pathway, provides opportunities for therapeutic invention. Here, we used structure‐based design to develop a new Syn3 peptidomimetic compound series that targets the PDZ3 domain of PSD‐95. The new compounds bind the PSD‐95 PDZ3 domain and adjoining αC helix with 7‐fold stronger affinity than prototype compound CN2097.