ACE

ACE is a zinc-dependent metallopeptidase and the central enzyme of the renin-angiotensin-aldosterone system (RAAS). It converts angiotensin I → angiotensin II by cleaving the C-terminal His-Leu dipeptide, and simultaneously inactivates bradykinin, substance P, and the anti-fibrotic tetrapeptide AcSDKP. As a target, ACE sits at the intersection of blood pressure, fibrosis, immune modulation, and - via AcSDKP regulation - extracellular matrix remodeling. Every peptide scaffold aimed at RAAS modulation, cardioprotection, or anti-fibrotic intervention touches this card.

Somatic ACE is a 1306-aa type-I transmembrane glycoprotein (~180 kDa with glycosylation) with two homologous catalytic domains: the C-domain drives angiotensin II production (Km 21 μM, kcat 18.8 s⁻¹ for Ang I); the N-domain preferentially cleaves bradykinin and AcSDKP. Both active sites share the canonical HEXXH zinc-binding motif. A separate germinal isoform expressed on sperm encodes only the C-domain equivalent. Membrane-bound enzyme is shed proteolytically to generate the circulating soluble form. The I/D polymorphism (287-bp Alu in intron 16) explains ~47% of plasma ACE variance: DD homozygotes carry roughly 2× the enzyme activity of II homozygotes, with downstream effects on angiotensin II tone and bradykinin half-life.

No peptide drug directly targets ACE - the approved inhibitors are small-molecule carboxylate, sulfhydryl, and phosphinic acid scaffolds (captopril, enalapril, lisinopril, ramipril). C-domain-selective inhibitors are in preclinical development to preserve bradykinin while blocking angiotensin II generation, reducing cough and angioedema liability. The anti-fibrotic peptide AcSDKP - cleaved exclusively by the ACE N-domain - is an active research scaffold: its protection via N-domain-selective inhibition suppresses cardiac and renal fibrosis in preclinical models. The HOPE trial (ramipril) showed 20–30% reduction in MI, stroke, and cardiovascular death, establishing ACE's causal role in cardiovascular endpoints beyond blood pressure. For peptide research, the most tractable recipes on this target involve N-domain-selective substrates, AcSDKP analogs, and bradykinin-potentiating peptides (BPPs) - the original leads from Bothrops jararaca venom that inspired the entire ACEi drug class.