Renin inhibition by substituted piperidines: A novel paradigm for the inhibition of monomeric aspartic proteinases?

Oefner, Christian; Binggeli, Alfred; Breu, Volker; Bur, Daniel; Jp, Clozel; D’Arcy, Allan; Dorn, Arnulf; Fischli, Walter; Grüninger, Fiona; Güller, Rolf; Hirth, Georges; Märki, HP; Mathews, Salima; Müller, Marcel; Ridley, RG; Stadier, H; Vieira, Eric; Wilhelm, M; Winkler, FK; Wostl, Wolfgang

doi:10.1016/s1074-5521(99)89004-8

Cited by 125 publications

(109 citation statements)

References 30 publications

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“…A similar pH profile was observed for the inhibition by pepstatin A (Fig. 2B), reconfirming that the enzyme-inhibitor complex is similar to the enzyme-substrate complex, and that pepstatin A binds to the monoprotonated form of the proteases, as has also been demonstrated by 13 C NMR (28,29), neutron Laue diffraction (30), and isothermal titration calorimetry (31) methods.…”

Section: Discussionsupporting

confidence: 81%

“…These peptidomimetic inhibitors usually show slow binding behavior, which could be attributed to tightening of the enzyme-inhibitor complex as a result of flap closing. Totally different conformational changes have been observed in the three-dimensional structure of the renin active site upon non-peptidic inhibitor binding (13). This novel binding pattern bares little resemblance to the ex- tended ␤-sheet structure of the substrate, but nevertheless renders potent inhibition of the enzyme.…”

Section: Discussionmentioning

confidence: 99%

“…These inhibitors usually are competitive with respect to the substrate peptide (11,12), and if the amino acid sequence of the natural peptidic substrate is available, optimization of such inhibitors is straightforward. The situation is more complex for non-peptidic inhibitors, where a significant distortion of the enzyme active center is observed upon inhibitor binding (13). These dramatic structural changes are difficult to predict, hence rational optimization of inhibitors is precluded in the absence of structural information.…”

mentioning

confidence: 99%

“…Recently a series of 4Ј-substituted piperidines has been identified as potent renin (14), plasmepsin (13), and pepsin (15) inhibitors. A renin crystal structure with a potent piperidine bound indicates significant conformational shift (opening) of the flap and relocation of the Trp39 side chain to accommodate the 4Ј substituent (13).…”

mentioning

confidence: 99%

“…A renin crystal structure with a potent piperidine bound indicates significant conformational shift (opening) of the flap and relocation of the Trp39 side chain to accommodate the 4Ј substituent (13). The protonated nitrogen of the piperidine moiety is positioned between the two catalytic aspartates making two strong hydrogen bonds.…”

mentioning

confidence: 99%

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Novel Inhibition of Porcine Pepsin by a Substituted Piperidine

Marcinkeviciene¹,

Kopcho²,

Yang³

et al. 2002

Journal of Biological Chemistry

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Biophys. 106, 234 -251), suggesting that the two inhibitors bind in a mutually exclusive fashion to pepsin. Fitting of the entire data set to the appropriate equation yielded an ␣ factor of 8 ؎ 1. The magnitude of this factor (ؕ > ␣ > 1) can be explained by a conformational distinction between the enzyme species that bind each inhibitor. The effects of pH on the inhibition constants for pepstatin A and the substituted piperidine also suggest that the inhibitors bind to distinct conformational forms of the enzyme. No inhibition by the piperidine was observed at acidic pH, while pepstatin A inhibition is maximal at low pH values. Inhibition by the piperidine was maximal when a group with pK 4.8 ؎ 0.2 was deprotonated and another group with pK 5.9 ؎ 0.2 was protonated. Most likely these two groups are the catalytic aspartates with perturbed ionization properties as a result of a significant and unique conformational change. Taken together, these data suggest that the enzyme can readily interconvert between two conformers, one capable of binding substrate and pepstatin A and the other capable of binding the substituted piperidine.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Novel Inhibition of Porcine Pepsin by a Substituted Piperidine

Marcinkeviciene¹,

Kopcho²,

Yang³

et al. 2002

Journal of Biological Chemistry

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Peptidomimetics for Drug Design

Estiarte

Rich

2003

Burger's Medicinal Chemistry and Drug Discovery

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The past and present role of peptidomimetics to drug discovery and protein design is summarized. The historical evolution of this area of research and the current state‐of‐the‐art research strategies are described. A detailed description of each of the peptidomimetics types that have appeared in the literature so far is discussed. Some examples are used to illustrate the drug design process that proceeds from the native peptide to a completely non‐peptide peptidomimetic structure. Special attention is given to important pharmaceutical targets such as the cysteine, metallo, serineor aspartic proteases, integrins, G‐protein–coupled receptors, etc. The principles currently used are highlighted in the discussions of some of the most successful examples. It is obvious that major progress in this area is primarily derived of recent advances in all aspects of science. Molecular modeling, X‐ray crystallography, and high field NMR have greatly contributed to this endeavor. Peptidomimetic inhibitors were traditionally developed by modifying peptide bonds, by mimicking the transition states for enzyme‐catalyzed reactions, or by constraining the conformational mobility of a peptide‐derived chain; the latter was used to overcome some of the pharmacokinetic barriers encountered in using peptides as drugs. Lately, these difficulties have been partially solved with rational drug design of de novo compounds. Several methods have been successfully applied, with noteworthy examples currently in clinical trials, and many others are expected in the near future. It would be wrong, however, to imply that this process is a universal panacea. New ideas are urgently needed to produce clinical candidates faster and to solve some of the undesired pharmacokinetic issues.

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Antihypertensives: Renin Inhibitors

Tice¹,

McGeehan²,

Claremon³

2010

Burger's Medicinal Chemistry and Drug Discovery

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Renin has been recognized as an attractive target for antihypertensive drugs since the 1950s. Intensive efforts in the 1980s focused on peptidomimetic hydroxy transition‐state isosteres led to many potent renin inhibitors. However, none of these compounds was developed as a drug. The advent of routine X‐ray crystallography of protein–ligand complexes provided additional insights that culminated in the discovery of aliskiren, a fully nonpeptidic renin inhibitor. Aliskiren, the first direct renin inhibitor to reach the market, was approved as an antihypertensive in 2007. Preliminary clinical trials suggest that aliskiren, and potentially other direct renin inhibitors, may have utility in end organ protection and congestive heart failure, in addition to hypertension.

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Renin inhibition by substituted piperidines: A novel paradigm for the inhibition of monomeric aspartic proteinases?

Cited by 125 publications

References 30 publications

Novel Inhibition of Porcine Pepsin by a Substituted Piperidine

Novel Inhibition of Porcine Pepsin by a Substituted Piperidine

Peptidomimetics for Drug Design

Antihypertensives: Renin Inhibitors

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