Reactome | MME:Zn2+ binds sacubitrilat

MME:Zn2+ binds sacubitrilat

Stable Identifier

R-HSA-9727607

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol, plasma membrane

ReviewStatus

5/5

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Neprilysin (MME) is responsible for the degradation of atrial and brain natriuretic peptides (NPPA and NPPB respectively), two blood pressure–lowering peptides that work by reducing blood volume (Richards et al. 1990). Sacubitril is an antihypertensive drug used in combination with valsartan for the treatment of hypertension and heart failure (Gu et al. 2010, Kobalava et al. 2016, Kanodia et al. 2020). Sacubitril is a prodrug that is activated to sacubitrilat (LBQ657) by de-ethylation via esterases (Shi et al. 2016). Sacubitrilat inhibits MME, leading to a lowering of hypertension (Zheng et al. 2021). Angiotensin receptor blockade (via valsartan) and neprilysin inhibition (via sacubitril) together may offer superior benefits for the treatment of hypertension and heart failure than ACE inhibitor monotherapy (McMurray et al. 2014).

Literature References

PubMed ID	Title	Journal	Year
19934029	Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi) Ksander, G, Gu, J, Ligueros-Saylan, M, Sarangapani, R, Maahs, S, Noe, A, Rigel, DF, Lin, TH, Al-Fayoumi, S, Chandra, P, Zheng, W, Dole, WP, Jeng, AY	J Clin Pharmacol	2010
2144260	Inhibition of endopeptidase EC 24.11 in humans. Renal and endocrine effects Cussans, N, Richards, M, Yandle, T, Sopwith, M, Ikram, H, Frampton, C, Espiner, E	Hypertension	1990
32506827	Safety, Pharmacokinetics, and Pharmacodynamics of TD-0714, a Novel Potent Neprilysin Inhibitor in Healthy Adult and Elderly Subjects Baldwin, RM, Bourdet, DL, Lo, A, Kanodia, J, Zhou, K, Colley, K	Clin Transl Sci	2020
26990595	Pharmacodynamic and Pharmacokinetic Profiles of Sacubitril/Valsartan (LCZ696) in Patients with Heart Failure and Reduced Ejection Fraction Albrecht, D, Averkov, O, Moiseev, V, Ayalasomayajula, S, Langenickel, TH, Rajman, I, Prescott, MF, Jordaan, P, Kotovskaya, Y, Pal, P, Chandra, P, Kobalava, Z, Pavlikova, E	Cardiovasc Ther	2016