PDZ domains are an adaptor or scaffold proteins involved in protein-protein interactions and modulation of numerous cellular process. The PDZ3 domain of the postsynaptic density-95 protein (PSD-95) is important in the development of neurobiological diseases, such as stroke associated with ischemic brain damage, psycho-stimulant addition, and Angelman syndrome (AS). A peptidomimetic CN2097 consists of a polyarginine peptide linked through a disulfide linker with a PDZ cyclic peptide containing a lactam ring and a β-alanine linker (R<sub>7</sub>-Cs-sC-YK[KTE(β-Ala)]V) was used to understand the function of PSD-95. The peptide forms unique contacts outside the canonical PDZ binding pocket. The limitation of current synthetic methodology prompt us to design efficient synthesis of CN2097 to provide sufficient amounts of CN2097 for preclinical studies. The PDZ domain cyclic peptide was synthesized by using Fmoc/tBu solid phase chemistry followed by cleavage of the peptide from the resin with in situ sulfur activation. This methodology provided a high yield of the peptide with activated cysteine that formed a disulfide linkage with polyarginine peptide containing a cysteine residue in the water to afford CN2097 in 6 h with 90% yield. CN2097 was used to evaluate neuroprotective activity against AS. AS characterize with a serve cognitive impairment and autism due to loss of expression of the maternally inherited allele of the Ube3A ubiquitin gene. The mice deficient of Ube3A gene produce low long term potentiation (LTP) which related with high activity-regulated cytoskeleton-associated protein (Arc/Arg3.1). The high level of arc interfer with brain-derived neurotrophic factor (BDNF) TrkB receptor signaling which induce LTP induction and maintenance. We found that CN2097 binds to PDZ domain of PSD-95 which decrease the interaction of Arc with PSD-95 to restore BDNF-induced TrkB/PSD-95 complex formation, signaling, and facilitate the induction of LTP in AS mice.

Efficient synthesis and neuroprotective activity of CN2097: A cyclic disulfide polyarginine peptidomimetic binding PDZ domain of PSD-95

251st National Meeting (2016)

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