Activated protein C: biased for translation.

Area of Science:

• Biochemistry and Molecular Biology
• Pharmacology
• Regenerative Medicine

Background:

• Activated protein C (APC) is a homeostatic blood protease with multifaceted physiological roles.
• APC exhibits antithrombotic, cytoprotective, and regenerative functions.
• APC's therapeutic potential has been explored in various preclinical injury models.

Purpose of the Study:

• To review the diverse therapeutic applications of APC and its variants.
• To elucidate the mechanisms underlying APC's beneficial effects.
• To highlight the development of APC variants with reduced bleeding risk for clinical translation.

Main Methods:

• Review of preclinical studies utilizing recombinant APC and its variants.
• Analysis of APC's interaction with protease-activated receptors (PARs) 1 and 3.
• Description of engineered APC variants, including 3K3A-APC, for reduced anticoagulant activity.

Main Results:

• APC demonstrates efficacy in preclinical models of ischemia/reperfusion, inflammation, sepsis, viral infections, diabetes, and radiation injury.
• APC modulates cell signaling and gene expression via PAR1 and PAR3 activation through biased signaling pathways.
• Engineered APC variants, such as 3K3A-APC, maintain therapeutic signaling while significantly reducing anticoagulant activity.

Conclusions:

• Activated protein C (APC) possesses broad therapeutic potential beyond anticoagulation.
• APC variants engineered for reduced bleeding risk, like 3K3A-APC, represent promising therapeutic candidates.
• Preclinical data support the translation of APC variants into novel clinical therapies, particularly for conditions like ischemic stroke.