Structure of neprilysin in complex with the active metabolite of sacubitril

Abstract

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.

Angioedema in heart failure patients treated with sacubitril/valsartan (LCZ696) or enalapril in the PARADIGM-HF study

“…The main reason for the difference between omapatrilat and sacubitril/valsartan may be the lower risk of angioedema with an ARB versus an ACE [6,8,11]. Additionally, the more specific inhibition of neprilysin may also contribute to a lower risk of angioedema [20][21][22][23][24].…”

Structures of soluble rabbit neprilysin complexed with phosphoramidon or thiorphan

“…The structures of several human neprilysin extracellular domains have been published in complex with various inhibitors, including phosphoramidon (Oefner et al, 2000(Oefner et al, , 2004, Glossop et al, 2011;Webster et al, 2014;Schiering et al, 2016). Most recently, a human structure free of any bound inhibitor or substrate has been reported (Moss et al, 2018).…”

Repurposing of existing FDA approved drugs for Neprilysin inhibition: An in-silico study

“…Both α-helical subdomains of NEP are connected with the linker region and essential catalytic triad are present in the central cavity of both subdomains. In the central cavity, the catalytically important zinc atom is coordinated with the side chains of amino acid residues HIS583, HIS587, and GLU646 [38, 27] . In the protein, the co-crystallized ligand, sacubitrilat, is bound to the active site of NEP and showed crucial interactions with HIS583, HIS587 and GLU646 residues.…”

“…The inhibitor binding pocket in the protein structure of the extracellular domain of human NEP (PDB ID: 5JMY ) has already been revealed by Schiering, Nikolaus, et al. [27] . The inhibitor binding pocket contains the catalytically essential triad of HIS583, HIS587 and GLU646.…”