Synthesis and evaluation of heteroarylalanine diacids as potent and selective neutral endopeptidase inhibitors

Glossop, Melanie S.; Bazin, Richard; Dack, Kevin N.; Fox, David; Macdonald, Graeme A.; Mills, Mark; Owen, Dafydd R.; Phillips, Chris; Reeves, Keith A.; Ringer, Tracy J.; Strang, Ross S.; Watson, Christine

doi:10.1016/j.bmcl.2011.03.109

Cited by 16 publications

(17 citation statements)

References 11 publications

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“…The amide directionality in LBQ657 is different relative to peptide substrate and inhibitors reported in published crystal structures7891011. In LBQ657, the –NH of the amide is attached to the chiral carbon atom, while in the inhibitors from crystal structures reported previously7891011, the attachment occurs via the amide carbonyl. It is interesting to note that for both types of amide, the nitrogen and oxygen atoms occupy similar positions in the complex structures and are engaged in the same type of interactions (Fig.…”

Section: Resultsmentioning

confidence: 83%

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Structure of neprilysin in complex with the active metabolite of sacubitril

Schiering

D’Arcy

Villard

et al. 2016

Sci Rep

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Sacubitril is an ethyl ester prodrug of LBQ657, the active neprilysin (NEP) inhibitor, and a component of LCZ696 (sacubitril/valsartan). We report herein the three-dimensional structure of LBQ657 in complex with human NEP at 2 Å resolution. The crystal structure unravels the binding mode of the compound occupying the S1, S1’ and S2’ sub-pockets of the active site, consistent with a competitive inhibition mode. An induced fit conformational change upon binding of the P1’-biphenyl moiety of the inhibitor suggests an explanation for its selectivity against structurally homologous zinc metallopeptidases.

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Section: Resultsmentioning

confidence: 83%

“…In recent years, several structures of the soluble extracellular domain of NEP complexed with inhibitors have become available7891011. In this report we describe the crystal structure of NEP in complex with LBQ657 and rationalize the selectivity of the compound relative to the homologous peptidases, endothelin converting enzyme (ECE-1) and neprilysin 2 (NEP2).…”

mentioning

confidence: 99%

Structure of neprilysin in complex with the active metabolite of sacubitril

Schiering

D’Arcy

Villard

et al. 2016

Sci Rep

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“…Large ligand induced flexibility of amino acid side chains is observed in the substrate binding site, with particularly Trp 693 functioning as a switch between the S1’ and S2’ pockets in wild-type NEP (Figure 8); (P1’ and P2’ dependency shown in Oefner et al ., [7], Glossop et al,[42]). In the crystal structure of the NEPv presented here, the two mutations have reduced the substrate binding sites S1’ and S2’ as well as decreased the binding site plasticity.…”

Section: Discussionmentioning

confidence: 99%

Engineering Neprilysin Activity and Specificity to Create a Novel Therapeutic for Alzheimer’s Disease

et al. 2014

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Neprilysin is a transmembrane zinc metallopeptidase that degrades a wide range of peptide substrates. It has received attention as a potential therapy for Alzheimer’s disease due to its ability to degrade the peptide amyloid beta. However, its broad range of peptide substrates has the potential to limit its therapeutic use due to degradation of additional peptides substrates that tightly regulate many physiological processes. We sought to generate a soluble version of the ectodomain of neprilysin with improved activity and specificity towards amyloid beta as a potential therapeutic for Alzheimer’s disease. Extensive amino acid substitutions were performed at positions surrounding the active site and inner surface of the enzyme and variants screened for activity on amyloid beta 1–40, 1–42 and a variety of other physiologically relevant peptides. We identified several mutations that modulated and improved both enzyme selectivity and intrinsic activity. Neprilysin variant G399V/G714K displayed an approximately 20-fold improved activity on amyloid beta 1–40 and up to a 3,200-fold reduction in activity on other peptides. Along with the altered peptide substrate specificity, the mutant enzyme produced a markedly altered series of amyloid beta cleavage products compared to the wild-type enzyme. Crystallisation of the mutant enzyme revealed that the amino acid substitutions result in alteration of the shape and size of the pocket containing the active site compared to the wild-type enzyme. The mutant enzyme offers the potential for the more efficient degradation of amyloid beta in vivo as a therapeutic for the treatment of Alzheimer’s disease.

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“…Several crystal structures of the soluble ectodomain in complex with various inhibitors have provided insight into the structure and specificity of NEP (Oefner et al, 2000, 2004, 2007; Sahli et al, 2005; Glossop et al, 2011; Schiering et al, 2016). The ectodomain consists of two α -helical lobes linked by interlacing polypeptide chains.…”

Section: Therapeutic Targets Of the Renin-angiotensin System Andmentioning

confidence: 99%

Novel Therapeutic Approaches Targeting the Renin-Angiotensin System and Associated Peptides in Hypertension and Heart Failure

et al. 2019

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Despite the success of renin-angiotensin system (RAS) blockade by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor (AT1R) blockers, current therapies for hypertension and related cardiovascular diseases are still inadequate. Identification of additional components of the RAS and associated vasoactive pathways, as well as new structural and functional insights into established targets, have led to novel therapeutic approaches with the potential to provide improved cardiovascular protection and better blood pressure control and/or reduced adverse side effects. The simultaneous modulation of several neurohumoral mediators in key interconnected blood pressure–regulating pathways has been an attractive approach to improve treatment efficacy, and several novel approaches involve combination therapy or dual-acting agents. In addition, increased understanding of the complexity of the RAS has led to novel approaches aimed at upregulating the ACE2/angiotensin-(1-7)/Mas axis to counter-regulate the harmful effects of the ACE/angiotensin II/angiotensin III/AT1R axis. These advances have opened new avenues for the development of novel drugs targeting the RAS to better treat hypertension and heart failure. Here we focus on new therapies in preclinical and early clinical stages of development, including novel small molecule inhibitors and receptor agonists/antagonists, less conventional strategies such as gene therapy to suppress angiotensinogen at the RNA level, recombinant ACE2 protein, and novel bispecific designer peptides.

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Synthesis and evaluation of heteroarylalanine diacids as potent and selective neutral endopeptidase inhibitors

Cited by 16 publications

References 11 publications

Structure of neprilysin in complex with the active metabolite of sacubitril

Structure of neprilysin in complex with the active metabolite of sacubitril

Engineering Neprilysin Activity and Specificity to Create a Novel Therapeutic for Alzheimer’s Disease

Novel Therapeutic Approaches Targeting the Renin-Angiotensin System and Associated Peptides in Hypertension and Heart Failure

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