Recent developments in the design of angiotensin‐converting enzyme inhibitors

Wyvratt, Matthew J.; Patchett, Arthur A.

doi:10.1002/med.2610050405

Cited by 261 publications

(175 citation statements)

References 137 publications

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“…However, the use of different methods and their associated modifications to test ACE inhibitory capacity makes difficult the direct comparison of IC 50 values from different studies when some reports do not detail the number of enzyme units used in the inhibition analysis or do not include an IC 50 value for an ACE inhibitory standard such as Captopril® (Murray, Walsh & FitzGerald, 2004). As an example, the dipeptide AlaPro has been reported with IC 50 values ranging from 29 to 230 M (Wyvratt & Patchett, 1985;Ichimura, Hu, Aita & Maruyama, 2003;Fuglsang, Nilsson & Nyborg, 2003).…”

Section: Ace Inhibitory Activity Of Synthetically Derived Peptidesmentioning

confidence: 99%

Contribution of Leu and Hyp residues to antioxidant and ACE-inhibitory activities of peptide sequences isolated from squid gelatin hydrolysate

et al. 2011

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** This centre has implemented and maintains a Quality Management System which fulfils the requirements of the ISO standard 9001:2000 AbstractSquid gelatin obtained from inner and outer tunics was hydrolyzed with Alcalase to isolate antioxidant peptide sequences. The ACE-inhibitory activity of the isolated peptides was also evaluated. After fractionation by ultrafiltration and size-exclusion chromatography into four fractions, the antioxidant activity of the peptide fractions was determined by radical scavenging ability and ferric reducing power. Fraction FIII showed the highest antioxidant activity, although slight differences could be expected in the antioxidant activity of the different fractions based on the amino acid composition.FIII was subjected to liquid chromatography and tandem mass spectrometry (LC-MS/MS) and two major compounds were identified: the compound with m/z 952.42, which could be mostly comprised by the carbohydrate fucose, and the peptide with m/z 1410.63. Three possible sequences were proposed for this peptide, and the contribution of Leu or Hyp residues to the antioxidant and ACE-inhibitory activities of the resulting sequence was evaluated. The presence of Leu residues in the peptide sequence in *Manuscript Click here to view linked References 2 replacement of Hyp seems to play an important role in the antioxidant and ACEinhibitory activity.

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Section: Ace Inhibitory Activity Of Synthetically Derived Peptidesmentioning

confidence: 99%

Contribution of Leu and Hyp residues to antioxidant and ACE-inhibitory activities of peptide sequences isolated from squid gelatin hydrolysate

et al. 2011

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“…It is worth noting that the potency of our best NS3/4A inhibitor (2 µM) is equivalent to the potency (IC 50 ) 4.9 and 2.4 µM, respectively) of N-carboxyalkyl or N-carboxymethyl dipeptide inhibitors of ACE lacking the P 1 side chain (46). Introduction of the proper P 1 side chain in the collected product leads to enalaprilat, and this is also the current direction of our design for NS3/4A.…”

Section: Discussionmentioning

confidence: 92%

“…In addition to binding into the active site, ACE inhibitors extended into the S 1 ′ and S 2 ′ subsites. Occupancy also of the S 1 subsite, although not strictly required for activity, greatly improved potency (46).…”

Section: Discussionmentioning

confidence: 99%

Prime Site Binding Inhibitors of a Serine Protease: NS3/4A of Hepatitis C Virus

et al. 2002

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Serine proteases are the most studied class of proteolytic enzymes and a primary target for drug discovery. Despite the large number of inhibitors developed so far, very few make contact with the prime site of the enzyme, which constitutes an almost untapped opportunity for drug design. In the course of our studies on the serine protease NS3/4A of hepatitis C virus (HCV), we found that this enzyme is an excellent example of both the opportunities and the challenges of such design. We had previously reported on two classes of peptide inhibitors of the enzyme: (a) product inhibitors, which include the P 6 -P 1 region of the substrate and derive much of their binding energy from binding of their C-terminal carboxylate in the active site, and (b) decapeptide inhibitors, which span the S 6 -S 4 ′ subsites of the enzyme, whose P 2 ′-P 4 ′ tripeptide fragment crucially contributes to potency. Here we report on further work, which combined the key binding elements of the two series and led to the development of inhibitors binding exclusiVely to the prime site of NS3/4A. We prepared a small combinatorial library of tripeptides, capped with a variety of constrained and unconstrained diacids. The SAR was derived from multiple analogues of the initial micromolar lead. Binding of the inhibitor(s) to the enzyme was further characterized by circular dichroism, site-directed mutagenesis, a probe displacement assay, and NMR to unequivocally prove that, according to our design, the bound inhibitor(s) occupies (occupy) the S′ subsite and the active site of the protease. In addition, on the basis of the information collected, the tripeptide series was evolved toward reduced peptide character, reduced molecular weight, and higher potency. Beyond their interest as HCV antivirals, these compounds represent the first example of prime site inhibitors of a serine protease. We further suggest that the design of an inhibitor with an analogous binding mode may be possible for other serine proteases.Serine proteases are perhaps the most studied class of proteolytic enzymes and a primary target for drug discovery. Despite the large number of inhibitors developed so far, very few make contact with the prime site of the enzyme. 1 Given that the starting point for inhibitor design is generally the substrate, this is not surprising, since for this class of enzymes the key determinants of substrate specificity reside in the P-region (1, 2-5). Therefore, developing inhibitors of serine proteases, which specifically target the prime site, is an almost untapped opportunity for drug design. In the course of our studies on the serine protease NS3/4A of hepatitis C virus (HCV), we found that this enzyme is an excellent example of both the opportunities and the challenges of such design.The target of our work is a key virally encoded enzyme, whose inhibition holds much promise for an effective anti-HCV therapy. Infection by hepatitis C virus (HCV) is widely recognized today as a huge public health concern, with more than 170 million people infe...

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“…Enalapril maleate is a monoethyl ester prodrug of the diacid enalaprilat. This prodrug (enalapril maleate) needs to undergo deesterification in vivo to produce its active form, enalaprilat (Wyvratt & Patchett, 1985). Studies in man indicate that absorption of enalapril maleate (61% oral availability) is rapid (peak plasma levels between 0.5-1.5 h after administration) and that enalapril maleate/enalaprilat is recovered intact (94%) from urine and faeces (apart from the bioactivation which is post-absorptive) .…”

Section: Resultsmentioning

confidence: 99%

“…The effects of enalapril maleate and lisinopril are both longer lasting than the effects of the less stable captopril . The structures of the first three orally-active ACE inhibitors (captopril, enalapril maleate and lisinopril) are similar or analogous to the dipeptide Ala-Pro (Wyvratt & Patchett, 1985) which is the C-terminal dipeptide of bradykinin-potentiating peptide Sa (BPP5a), a potent inhibitor of ACE activity isolated from snake venom (Cheung et al, 1980;Wyvratt & Patchett, 1986). Studies in rat jejunum using the single-pass perfusion method have suggested that the significant levels of absorption of these three ACE inhibitors across the intestinal epithelial wall is due to transport via the intestinal di/tripeptide carrier (Hu & Amidon, 1988;Friedman & Amidon, 1989a,b).…”

Section: Resultsmentioning

confidence: 99%

Angiotensin‐converting enzyme (ACE) inhibitor transport in human intestinal epithelial (Caco‐2) cells

Thwaites

Cavet

Hirst

et al. 1995

British J Pharmacology

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1 The role of proton-linked solute transport in the absorption of the angiotensin-converting enzyme (ACE) inhibitors captopril, enalapril maleate and lisinopril has been investigated in human intestinal epithelial (Caco-2) cell monolayers. 2 In Caco-2 cell monolayers the transepithelial apical-to-basal transport and intracellular accumulation (across the apical membrane) of the hydrolysis-resistant dipeptide, glycylsarcosine (Gly-Sar), were stimulated by acidification (pH 6.0) of the apical environment. In contrast, transport and intracellular accumulation of the angiotensin-converting enzyme (ACE) inhibitor, lisinopril, were low (lower than the paracellular marker mannitol) and were not stimulated by apical acidification.

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Recent developments in the design of angiotensin‐converting enzyme inhibitors

Cited by 261 publications

References 137 publications

Contribution of Leu and Hyp residues to antioxidant and ACE-inhibitory activities of peptide sequences isolated from squid gelatin hydrolysate

Contribution of Leu and Hyp residues to antioxidant and ACE-inhibitory activities of peptide sequences isolated from squid gelatin hydrolysate

Prime Site Binding Inhibitors of a Serine Protease: NS3/4A of Hepatitis C Virus

Angiotensin‐converting enzyme (ACE) inhibitor transport in human intestinal epithelial (Caco‐2) cells

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