Design of angiotensin converting enzyme inhibitors

Cushman, David; Ondetti, Miguel A.

doi:10.1038/13423

Cited by 197 publications

(161 citation statements)

References 19 publications

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“…However, the sequence of the ACE inhibitors present in B. jararaca, Agkistrodon halys blomhoffii, and other venoms stimulated a systematic study of peptide derivatives to inhibit ACE (Ondetti and Cushmen, 1981). The structure-activity analysis of these synthetic peptides provided insight into the catalytic site of ACE, and ultimately indicated that the optimal carboxyl-terminal amino acid sequence of ACE inhibitors was Phe-Ala-Pro (Cushman and Ondetti, 1999). Even more important than any particular structure, these studies led to an understanding of certain basics necessary for a successful ACE inhibitor.…”

Section: A Development Of First-generation Inhibitorsmentioning

confidence: 99%

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

et al. 2012

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Section: A Development Of First-generation Inhibitorsmentioning

confidence: 99%

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

et al. 2012

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“…Lisinopril was first designed by a simple ''paper and pencil'' model of substrate and inhibitor binding to the enzyme (29), and ultimately mapped at 2 A°with an X-ray crystal structure showing how it binds to human ACE (30). ACE inhibitors afford the opportunity when given in routine therapeutic doses to raise large numbers of antigen specific Treg cells with strong clinical efficacy.…”

Section: Discussionmentioning

confidence: 99%

Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity

Platten

Youssef²,

Hur³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

290

254

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The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure. The octapeptide angiotensin II (AII) is proteolytically processed from the decapeptide AI by angiotensin-converting enzyme (ACE), and then acts via angiotensin type 1 and type 2 receptors (AT1R and AT2R). Inhibitors of ACE and antagonists of the AT1R are used in the treatment of hypertension, myocardial infarction, and stroke. We now show that the RAAS also plays a major role in autoimmunity, exemplified by multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Using proteomics, we observed that RAAS is up-regulated in brain lesions of MS. AT1R was induced in myelin-specific CD4 ؉ T cells and monocytes during autoimmune neuroinflammation. Blocking AII production with ACE inhibitors or inhibiting AII signaling with AT1R blockers suppressed autoreactive TH1 and TH17 cells and promoted antigenspecific CD4؉FoxP3؉ regulatory T cells (Treg cells) with inhibition of the canonical NF-B1 transcription factor complex and activation of the alternative NF-B2 pathway. Treatment with ACE inhibitors induces abundant CD4؉FoxP3؉ T cells with sufficient potency to reverse paralytic EAE. Modulation of the RAAS with inexpensive, safe pharmaceuticals used by millions worldwide is an attractive therapeutic strategy for application to human autoimmune diseases. multiple sclerosis ͉ lisinopril ͉ FoxP3 ͉ AT1R

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“…Captopril([S]-1-[3-mercapto-2-methyl-1-oxo-propyl]-L-proline) is the first marketed orally active angiotensin-converting enzyme (ACE) inhibitor designed to treat hypertension by blocking the conversion of angiotensin I (Ang I) into angiotensin II (Ang II) Ondetti et al, 1977;Cushman and Ondetti, 1999). It is widely used in the treatment of cardiovascular diseases, including high blood pressure, heart failure, coronary artery diseases, renal failure.…”

Section: Introductionmentioning

confidence: 99%

Captopril suppresses inflammation in endotoxin-induced uveitis in rats

Ilieva

Ohgami

Jin

et al. 2006

Experimental Eye Research

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Condensed title: The anti-inflammatory effect of captopril Key words: Captopril, rennin-angiotensin system, uveitis, anti-inflammatory agent. anti-inflammatory action, on which we focused our attention. The aim of the present study was to investigate the efficacy of captopril on endotoxin induced uveitis (EIU) in rats. We investigated its effect upon cellular infiltration and protein leakage, as well as on the concentration of tumor necrosis factor-α (TNF-α), nitric oxide (NO), prostaglandin E2 (PGE2), monocyte chemoattractant protein-1 (MCP-1) in the anterior chamber. In addition, we checked its effect on activation of nuclear factor kappa B (NF-κB) in iris and ciliary body (ICB) cells in vivo.EIU was induced in male Lewis rats by a footpad injection of lipopolysaccharide (LPS). One hour after the LPS inoculation, either 1 mg/kg, 10 mg/kg or 100 mg/kg captopril were injected intravenously. 24 hours later, the aqueous humor was collected from both eyes, and the number of infiltrating cells and protein concentration in the aqueous humor were determined. Levels of TNF-α, PGE2, NO and MCP-1 were determined by enzyme-linked immunosorbent assay. On some eyes, after enucleation, immunohistochemical staining with a monoclonal antibody against activated NF-κB was performed.Captopril treatment significantly decreased the inflammatory cells infiltration, the level of protein, concentrations of TNF-α, PGE2, NO and MCP-1 in the aqueous humor.The number of activated NF-κB-positive cells was lower in ICB of the rats treated with captopril 3 hours after the LPS injection.The present results indicate that captopril suppresses the inflammation in EIU by inhibiting the NF-κB-dependent pathway and the subsequent production of pro-inflammatory mediators.

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Design of angiotensin converting enzyme inhibitors

Cited by 197 publications

References 19 publications

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity

Captopril suppresses inflammation in endotoxin-induced uveitis in rats

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