CPP-conjugated Anti-apoptotic Peptides as Therapeutic Tools of Ischemia-reperfusion Injuries

Acute myocardial infarction (AMI) is a frequent and disabling disease, which is the first cause of cardiovascular mortality worldwide. Infarct size is a major determinant of myocardial functional recovery and mortality after AMI. Limitation of infarct size thus appears as an appropriate strategy to prevent post-ischemic heart failure and improve survival. Reperfusion is the only treatment recommended to reduce infarct size but despite obvious benefits, it may also have deleterious effects called ischemia-reperfusion (IR) injury including myocyte cell death. Proteins involved in the apoptosis cascade generally interact over large surfaces lacking well-defined pockets. Therefore, inhibitory peptides are optimal biomolecules to target these large protein surfaces, they are often more selective to their target than conventional small organic molecules, and they can be tailored for optimal affinity or desired metabolic property. Since peptides do not cross freely biological membranes, they are generally administered in association with cell penetrating peptides (CPPs) and with homing peptides (HPs) for selective organs or tissues targeting. As a first approach in vivo, we made use of the already known BH4 peptidic inhibitor of the mitochondrial apoptotic pathway, which showed cardioprotective properties in a murine model of AMI after a single bolus of intravenous administration. More importantly, similar peptidic strategies and tools are likely to be adaptable to many other situations in which cells have to be protected from apoptosis such as stroke or organ transplantation.