CN-105: A Comprehensive Monograph on a Dual-Mechanism Apolipoprotein E Mimetic for Acute Neurological Injury

Executive Summary

CN-105 is an investigational, first-in-class, small molecule neuroprotective agent currently in clinical development for the treatment of acute brain injuries, primarily intracerebral hemorrhage (ICH). It is a synthetic pentapeptide with the sequence Acetyl-Valine-Serine-Arginine-Arginine-Arginine-NH2 ($Ac-VSRRR-NH_{2}$), rationally designed as a mimetic of apolipoprotein E (apoE), a key endogenous mediator of neuroinflammation and recovery in the central nervous system (CNS). The initial scientific rationale for CN-105 was to emulate the adaptive, anti-inflammatory, and neuroprotective functions of the apoE3 protein isoform, thereby counteracting the cascade of secondary brain injury that follows an acute neurological event. This cascade, characterized by glial activation, cytokine release, oxidative stress, and neuronal excitotoxicity, represents a critical and currently unaddressed therapeutic target in conditions like ICH, for which treatment remains largely supportive.

Subsequent mechanistic investigations have revealed a more complex, dual-pronged mechanism of action. In addition to its function as an apoE agonist that downregulates neuroinflammatory pathways, CN-105 also acts as a direct antagonist of nicotinic acetylcholine receptors (nAChRs). This secondary mechanism contributes to its neuroprotective profile by reducing excitotoxicity through the suppression of presynaptic glutamate release. However, this nAChR antagonism is also mechanistically linked to the drug's primary dose-limiting toxicity—respiratory suppression—observed at supratherapeutic doses in preclinical models, creating a narrow therapeutic window that must be carefully navigated.