Angiotensin (1-7) vs SS-31

Binds Mas receptor (MasR), activating nitric oxide synthase and reducing oxidative stress. Opposes TGF-β and angiotensin II signaling to reduce fibrosis. Enhances insulin sensitivity and provides cardiovascular protection.

Angiotensin-(1-7) [Ang-(1-7)] is an endogenous heptapeptide hormone generated primarily through cleavage of angiotensin II by ACE2, functioning as a counter-regulatory arm of the renin-angiotensin system (RAS) by binding the Mas receptor to promote vasodilation, anti-fibrotic, anti-inflammatory, and cardioprotective effects that oppose the vasoconstrictive actions of angiotensin II. Ang-(1-7) acts through the ACE2/Mas receptor axis to reduce oxidative stress, attenuate NF-kB-mediated inflammation, and suppress TGF-beta fibrosis signaling; the ACE2/Ang-(1-7)/Mas axis has emerged as a key regulatory pathway in cardiovascular and metabolic disease, and gained renewed research attention given ACE2's role as the SARS-CoV-2 entry receptor. A Phase 1-2 randomized clinical trial of Ang-(1-7) infusion in COVID-19 ICU patients reported preliminary safety, tolerability, and dose-response data, providing the primary indexed human pharmacokinetic evidence; broader cardiovascular protective applications are supported by preclinical data but have not been established by completed Phase 3 trials. Ang-(1-7) has no FDA approval and no approved therapeutic indication in any jurisdiction; it is an endogenous peptide under active clinical investigation as a candidate for cardiovascular, metabolic, and inflammatory conditions, with emerging human safety data but an incomplete evidence base for any specific approved clinical use.

Targets cardiolipin in inner mitochondrial membrane; stabilizes cristae structure; enhances electron transport chain efficiency; reduces mitochondrial ROS

SS-31 (elamipretide; Szeto-Schiller peptide 31; MTP-131; bendavia) is a synthetic cardiolipin-targeting tetrapeptide that selectively concentrates in the inner mitochondrial membrane through electrostatic interaction with cardiolipin, where it stabilizes cristae ultrastructure, preserves electron transport chain assembly, and reduces mitochondrial reactive oxygen species production to protect against ischemic and metabolic mitochondrial injury. By binding cardiolipin at the inner mitochondrial membrane, SS-31 maintains the protein-lipid interactions required for efficient electron transport chain supercomplex formation, preserving cytochrome c association with complexes I–IV, reducing electron leak, and sustaining the proton gradient required for ATP synthase activity — thereby protecting energy production in cardiomyocytes, neurons, and renal tubular cells under ischemic or oxidative stress. A randomized, placebo-controlled trial published in Circulation Heart Failure demonstrated that elamipretide improved cardiac function in patients with heart failure with reduced ejection fraction, and a Phase 2a trial published in Circulation Cardiovascular Interventions provided additional human evidence of mitochondrial protection in the context of renal artery stenosis revascularization. Elamipretide has not received FDA approval; it has received rare pediatric disease designation for Barth syndrome and has been studied in multiple Phase 2 trials including heart failure, primary mitochondrial myopathy, and geographic atrophy, with ongoing Phase 3 development programs as of 2025.