Angiotensin I-converting enzyme (ACE) inhibition has revolutionised cardiovascular care, yet classical inhibitors face safety and efficacy challenges. Here, Professors Ravi Acharya and Edward Sturrock review the historical foundation of ACE inhibition, the present landscape of structural and therapeutic innovations, and the future clinical promise for cardiovascular diseases and beyond.
Angiotensin I-converting enzyme (ACE) is central to cardiovascular medicine. Since the advent of captopril in 1977,1 ACE inhibitors have revolutionised the management of hypertension, heart failure and chronic kidney disease.2
ACE inhibitors block the conversion of angiotensin I to the potent vasoconstrictor angiotensin II, while simultaneously preserving vasodilatory peptides such as bradykinin. This seemingly simple and well-understood activity underscores the utility of ACE inhibitors in treating a wide range of diseases.3
Today, advances in molecular biology, structural biochemistry and computational drug design are redefining what ACE inhibition can achieve. Beyond classical blockade, new strategies that target individual domains, exploit allosteric sites and even combine dual pathways to improve drug efficacy and tolerability are being developed.
Development of early ACE inhibitors
The renin–angiotensin–aldosterone system (RAAS) is a tightly regulated hormonal cascade that influences vascular tone, electrolyte balance and extracellular fluid homeostasis. The role of ACE in RAAS is to catalyse the conversion of angiotensin I to angiotensin II, while also degrading bradykinin and other peptides.4
In the late 1970s, Ondetti and colleagues pioneered the rational design of ACE inhibitors, drawing parallels between ACE and carboxypeptidase A.1 Their efforts yielded captopril, the first orally active ACE inhibitor.
Despite its sulfhydryl-related side effects, captopril paved the way for more refined carboxylate-based inhibitors, such as enalapril and lisinopril,2 and later phosphinate analogues, such as fosinopril.
By the late 1980s and early 1990s, ACE inhibitors were firmly established as cornerstones of hypertension and heart failure management. Clinical trials confirmed their ability to reduce morbidity and mortality, slow renal disease progression and attenuate vascular remodelling. Yet challenges soon emerged: incomplete RAAS blockade, cough, angioedema and variable tolerability limited their universal application.
Illuminating ACE at the atomic level
Early insights into the structure of ACE came from X-ray crystallography of isolated ACE domains.
Somatic ACE (sACE) comprises two homologous catalytic domains: the N-domain (nACE) and the C-domain (cACE). Both share approximately 60% sequence identity and the conserved HExxH zinc-binding motif. Yet, they differ in substrate specificity, chloride dependence and physiological roles.4
cACE predominantly generates angiotensin II and regulates blood pressure, whereas nACE clears peptides such as N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), conferring antifibrotic and anti-inflammatory effects. High-resolution crystal structures of these domains have revealed inhibitor binding modes, domain-specific interactions and chloride-induced allosteric regulation.3
More recently, cryo-electron microscopy (cryo-EM) has captured full-length glycosylated ACE, exposing its dimerisation, dynamic conformational shifts and novel allosteric sites.5,6 These findings broaden the landscape for rational drug design.
Mechanistic insights and adverse effects
ACE inhibitors act as competitive antagonists, with inhibitory constants in the nanomolar range.3 ACE inhibitors have a dual action, reducing angiotensin II-mediated vasoconstriction while enhancing bradykinin-driven vasodilation, which distinguishes them from angiotensin receptor blockers. This duality, however, underpins common adverse effects.
Side effects can include persistent cough, dizziness and hyperkalaemia and, in some cases, angioedema.7 The accumulation of bradykinin and substance P is implicated in these outcomes.8
Moreover, the phenomenon of ‘ACE inhibitor escape’, during which persistent angiotensin II production occurs via alternative enzymes such as chymase, highlights the limitations of current drugs. These issues have driven the pursuit of next-generation inhibitors with greater specificity and fewer side effects.
Present innovations in ACE inhibition
Domain-selective inhibitors
A significant recent advance has been the recognition that nACE and cACE can be targeted separately. cACE-selective inhibitors may retain antihypertensive efficacy while lowering the incidence of bradykinin-mediated cough and angioedema.7
nACE-selective inhibitors could increase protective Ac-SDKP levels, offering novel therapies for fibrosis, renal disease and even adjunctive cancer treatments without significant effects on blood pressure.3 Promising prototypes include RXPA380 (cACE-selective) and RXP407 (nACE-selective).
Modified lisinopril analogues such as Lis-W have demonstrated selective blood pressure reduction without elevating bradykinin.3 However, pharmacokinetic challenges, particularly rapid renal clearance, remain barriers to clinical translation.
Dual ACE/NEP vasopeptidase inhibitors
Given the interplay between RAAS and the natriuretic peptide system, dual inhibition of ACE and neprilysin (NEP) has been explored.
Omapatrilat, the first vasopeptidase inhibitor, demonstrated superior blood pressure reduction but failed in large trials due to excess angioedema.3 Refined approaches now focus on cACE-selective/NEP inhibitors, to preserve bradykinin metabolism via nACE while enhancing levels of natriuretic peptide.
Preclinical combinations such as Lis-W with sacubitril show encouraging results in reducing hypertension and improving cardiac function.9
Allosteric inhibition
Allosteric modulation offers an alternative to direct zinc site blockade. Structural mapping via cryo-EM identified at least seven potential allosteric sites.5 Targeting these exosites could fine-tune enzyme activity, reduce off-target effects and bypass resistance mechanisms.
Early proof-of-concept studies suggest opportunities for allosteric inhibitors to alter dimerisation, substrate recognition or domain crosstalk.
Future clinical promise of ACE inhibition
The trajectory of ACE inhibition suggests several promising future directions for therapeutic development.
A key area is the design of refined domain-selective agents and multitarget inhibitors. cACE inhibitors with improved safety profiles could replace traditional pan-selective ACE drugs for hypertension and heart failure. nACE inhibitors may emerge as disease-modifying therapies in pulmonary fibrosis, kidney disease and inflammatory cardiomyopathies.3
Dual cACE/NEP inhibitors, or combined inhibitors with endothelin-converting enzyme, could offer synergistic modulation of the RAAS and natriuretic peptide pathways.10
Further innovation may come from the development of allosteric and exosite-targeting drugs. By disrupting ACE dimerisation or selectively modulating non-catalytic domains, these agents could offer therapeutic benefits without delivering full RAAS blockade.5
The integration of ACE inhibition with precision medicine strategies holds considerable promise. Advances in computational modelling and mutagenesis studies may pave the way for tailoring ACE inhibitors to individual patient genotypes, thereby optimising personalised care.11
The therapeutic potential of ACE inhibitors may extend beyond cardiovascular disease. Given the role of ACE in immune regulation, reproductive function and tissue remodelling, selective inhibitors may find applications in oncology, reproductive medicine and chronic inflammatory disorders.11
Notably, beyond its classical role in converting angiotensin I to angiotensin II, ACE is also capable of degrading amyloid-β (Aβ) peptides, which are central to Alzheimer’s disease pathology. Specifically, nACE cleaves Aβ more efficiently than cACE, suggesting that ACE may have a neuroprotective role by limiting Aβ accumulation and fibril formation in the brain.12,13
Conclusion
From captopril’s debut to the sophisticated design of domain-selective and allosteric modulators, ACE inhibitors embody the interplay between science and clinical practice. Structural breakthroughs have enabled a new generation of rationally designed therapies that are poised to overcome the limitations of current drugs.
At the clinical level, the potential for safer, more targeted ACE inhibition could transform the management of hypertension, heart failure, renal disease and fibrosis and may lead to the discovery of novel treatment options for cancer and other diseases.
Upcoming challenges include translating these molecular innovations into well-tolerated and durable treatments that continue the legacy of ACE inhibition as one of the great success stories in cardiovascular medicine.
Authors
K Ravi Acharya PhD
Professor of structural biology, Department of Life Sciences, University of Bath, UK
Edward D Sturrock PhD
Professor of medical biochemistry, Department of Integrative Biomedical Sciences, and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa
References
- Ondetti MA et al. Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. Science 1977;196:441–4.
- Patchett AA et al. A new class of angiotensin-converting enzyme inhibitors. Nature 1980;288:280–
- Acharya KR, Gregory KS, Sturrock ED. Advances in the structural basis for angiotensin1-converting enzyme (ACE) inhibitors. Biosci Rep 2024;44:BSR20240130.
- Acharya KR et al. ACE revisited. A new target for structure-based drug design. Nat Rev Drug Discov 2003;2:891–902.
- Lubbe L et al. Cryo-EM reveals mechanisms of angiotensin I-converting enzyme allostery and dimerisation. EMBO J 2022;41:e110550.
- Manci JM et al. Dimerisation and dynamics of angiotensin-I converting enzyme revealed by cryo-EM and MD simulations. eLife 2025;14:RP106044.
- Morimoto T et al. An evaluation of risk factors for adverse drug events associated with angiotensin-converting enzyme inhibitors. J Eval Clin Pract 2004;10(4):499–509.
- Nussberger J et al. Plasma bradykinin in angio-oedema. Lancet 1998;351(9117):1693–7.
- Alves-Lopes R et al. Selective inhibition of the C-domain of ACE (Angiotensin-Converting Enzyme) combined with inhibition of NEP (Neprilysin). A potential new therapy for hypertension. Hypertension 2021;78:604–16.
- Arendse LB et al. Novel therapeutic approaches targeting the renin-angiotensin system and associated peptides in hypertension and heart failure. Pharmacol Rev 2019;71:539–
- Rao VN. et al. Diverse biological functions of the renin-angiotensin system. Med Res Rev 2024;44:587–605.
- Kryukova OV et al. Effects of Angiotensin-I-converting enzyme (ACE) mutations associated with Alzheimer’s disease on blood ACE phenotype. Biomedicines 2024;12: 2410.
- Larmuth KM et al. Kinetic and structural characterisation of amyloid-β peptide hydrolysis by human angiotensin-1-converting enzyme. FEBS J 2016;283:1060–76.
This article was originally published by our sister publication Hospital Healthcare Europe.
