Attacking neurodegeneration and promoting neuroprotection have been the holy grail in neurology for almost 20years and represent an area of high unmet medical need. However, indications like Alzheimer's disease and stroke are areas in drug development fraught with failure. This review will highlight three CNS peptide programs which are tackling targets and indications in which traditional small molecule approaches have been difficult and challenging. The targets for these potential peptide therapeutics include the NMDA receptor, γ-secretase, and cyclin-dependent kinase in which direct inhibition has resulted in on-target (not compound related) problems. For example, direct inhibition of γ-secretase has resulted in gastrointestinal abnormalities and inhibition of the NMDA receptor can result in hallucinations, dizziness, out-of-body sensations, and nightmares. When confronted with show-stopping side effects, the CNS peptide programs profiled in this review strike the problem with intervention and disruption of selective protein-protein interactions. The goal of these peptide programs is to produce selective therapeutics with a better safety profile.
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