Targeting the Protective Arm of the Renin-Angiotensin System: Focused on Angiotensin-(1–7)

Abstract

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 would be extremely valuable. Such approaches could improve systemic bioavailability and enhance therapeutic effects. The renin-angiotensin system (RAS) is a hormonal system within the body 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 the homeostasis of the body's physiological function. Activation of the RAS results in the suppression of its protective arm that 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)), a RAS critical regulatory peptide, augments the protective arm and restores balance hampered by its enzymatic and chemical instability. Several attempts to increase the half-life and efficacy of this heptapeptide using more stable analogs and different drug delivery approaches have been made. This review article provides an overview of efforts targeting the RAS protective arm. It provides a critical analysis of Ang-(1-7) or its homologs' novel drug delivery systems using different administration routes, their pharmacological characterization, and therapeutic potential in various clinical settings.Significance Statement: Ang-(1-7) is a unique peptide component of the RAS system with vast potential for clinical applications that modulate various inflammatory diseases. Novel Ang-(1-7) peptide drug delivery could compensate its lack of stability for effective clinical application.

Atomistic molecular insight on Angiotensin-(1-7) interpeptide interactions

“…Angiotensin-(1-7) (Ang- (1)(2)(3)(4)(5)(6)(7)) is an endogenous bio-active therapeutic heptapeptide involved in many clinical conditions ranging from cancer, cardiovascular diseases, pulmonary diseases, diabetes and COVID-19, 8,9 which guarantees its physiological and therapeutically relevance. Ang-(1-7) shows a β-sheet structure in solution, with a bend stabilized by interactions between residues Val3 and Tyr4 according to circular dichroism and NMR data.…”

Atomistic Molecular Insights into Angiotensin-(1-7) Interpeptide Interactions

“…Angiotensin-(1-7) [Ang-(1-7)] is an endogenous bioactive therapeutic heptapeptide involved in many clinical conditions ranging from cancer, cardiovascular diseases, pulmonary diseases, diabetes, and COVID-19, , which guarantees its physiological and therapeutic relevance. It has been previously reported that Ang-(1-7) exhibits a β-sheet structure in solution, with a bend that is stabilized by interactions between VAL3 and TYR4 residues, as indicated by circular dichroism and NMR data .…”

“…Abe et al, studied the pHdependent aggregate forms and conformation of Alzheimer's amyloid peptide and showed that low pH stabilizes the peptide conformation and prevents aggregation due to electrostatic effects. 10 Angiotensin-(1-7) [Ang- (1)(2)(3)(4)(5)(6)(7)] is an endogenous bioactive therapeutic heptapeptide involved in many clinical conditions ranging from cancer, cardiovascular diseases, pulmonary diseases, diabetes, and COVID-19, 11,12 which guarantees its physiological and therapeutic relevance. It has been previously reported that Ang-(1-7) exhibits a β-sheet structure in solution, with a bend that is stabilized by interactions between VAL3 and TYR4 residues, as indicated by circular dichroism and NMR data.…”

Inhibition of the postsynaptic density protein 95 on the protective effect of Ang-(1-7)–Mas on cerebral ischaemia injury

“…RAS is an important system for regulating hydroelectrolyte balance and blood pressure 5. RAS contains two axes, that is, ACE-angiotensin II-angiotensin type 1 receptor and ACE2-angiotensin-(1-7) (Ang-(1-7))-Mas axes, which show opposite effects 6 7. Ang-(1-7) and Mas are abundant in the nervous system 8 9.…”

“… 5 RAS contains two axes, that is, ACE-angiotensin II-angiotensin type 1 receptor and ACE2-angiotensin-(1-7) (Ang-(1-7))-Mas axes, which show opposite effects. 6 7 Ang-(1-7) and Mas are abundant in the nervous system. 8 9 Recent studies found that the ACE2–Ang-(1-7)–Mas axis has a protective effect on the cerebral ischaemia disease.…”