%0 Journal Article %A Sana Khajehpour %A Ali Aghazadeh-Habashi %T Targeting the Protective Arm of the Renin-Angiotensin System: Focused on Angiotensin-(1-7) %D 2021 %R 10.1124/jpet.120.000397 %J Journal of Pharmacology and Experimental Therapeutics %P JPET-MR-2020-000397 %X The in vivo application and efficacy of many therapeutic peptides is limited, due to their instability and proteolytic degradation. Novel strategies for developing therapeutic peptides with higher stability toward proteolytic degradation need to be introduced. Such approaches could improve systemic bioavailability and enhance therapeutic effects. The renin-angiotensin system (RAS) is a hormonal system within the body that is essential for the regulation of blood pressure and fluid balance. The RAS is composed of two opposing classical and protective arms. The balance between these two arms is critical for homeostasis of the physiological function of the body. Activation of the RAS results in the suppression of its protective arm, which has been reported in inflammatory and pathological conditions such as arthritis, cardiovascular diseases, diabetes, and cancer. Clinical application of the Angiotensin-(1-7) (Ang-(1-7)), one of the RAS critical regulatory peptides, for augmentation of the protective arm and restoration of the balance is hampered by its enzymatic and chemical instability. There have been several attempts to increase the half-life and efficacy of this heptapeptide using more stable analogs and different drug delivery approaches. This review article provides an overview of the attempts on targeting the RAS protective arms. It provides a critical analysis of novel drug delivery systems of Ang-(1-7) or its homologs through different routes of administration, their pharmacological characterization, and therapeutic potential in various clinical settings. Significance Statement Ang-(1-7) as a unique peptide component of the RAS system has a vast potential for clinical applications in modulating various inflammatory diseases. Its lack of stability could be compensated by novel peptide drug delivery for effective clinical application. %U https://jpet.aspetjournals.org/content/jpet/early/2021/01/25/jpet.120.000397.full.pdf