6thp
From Proteopedia
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== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/NEP_HUMAN NEP_HUMAN]] Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids. Biologically important in the destruction of opioid peptides such as Met- and Leu-enkephalins by cleavage of a Gly-Phe bond. Able to cleave angiotensin-1, angiotensin-2 and angiotensin 1-9. Involved in the degradation of atrial natriuretic factor (ANF). Displays UV-inducible elastase activity toward skin preelastic and elastic fibers.<ref>PMID:2531377</ref> <ref>PMID:15283675</ref> <ref>PMID:20876573</ref> | [[http://www.uniprot.org/uniprot/NEP_HUMAN NEP_HUMAN]] Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids. Biologically important in the destruction of opioid peptides such as Met- and Leu-enkephalins by cleavage of a Gly-Phe bond. Able to cleave angiotensin-1, angiotensin-2 and angiotensin 1-9. Involved in the degradation of atrial natriuretic factor (ANF). Displays UV-inducible elastase activity toward skin preelastic and elastic fibers.<ref>PMID:2531377</ref> <ref>PMID:15283675</ref> <ref>PMID:20876573</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Inhibition of neprilysin (NEP) is widely studied as a therapeutic target for the treatment of hypertension, heart failure, and kidney disease. Sacubitril/valsartan (LCZ696) is a drug approved to reduce the risk of cardiovascular death in heart failure patients with reduced ejection fraction. LBQ657 is the active metabolite of sacubitril and an inhibitor of NEP. Previously, we have reported the crystal structure of NEP bound with LBQ657, whereby we noted the presence of a subsite in S1' that has not been explored before. We were also intrigued by the zinc coordination made by one of the carboxylic acids of LBQ657, leading us to explore alternative linkers to efficiently engage zinc for NEP inhibition. Structure-guided design culminated in the synthesis of selective, orally bioavailable, and subnanomolar inhibitors of NEP. A 17-fold boost in biochemical potency was observed upon addition of a chlorine atom that occupied the newly found subsite in S1'. We report herein the discovery and preclinical profiling of compound 13, which paved the path to our clinical candidate. | ||
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| + | Structure-Guided Design of Substituted Biphenyl Butanoic Acid Derivatives as Neprilysin Inhibitors.,Kawanami T, Karki RG, Cody E, Liu Q, Liang G, Ksander GM, Rigel DF, Schiering N, Gong Y, Coppola GM, Iwaki Y, Sun R, Neubert A, Fan L, Ingles S, D'Arcy A, Villard F, Ramage P, Jeng AY, Leung-Chu J, Liu J, Beil M, Fu F, Chen W, Cumin F, Wiesmann C, Mogi M ACS Med Chem Lett. 2020 Jan 27;11(2):188-194. doi:, 10.1021/acsmedchemlett.9b00578. eCollection 2020 Feb 13. PMID:32071687<ref>PMID:32071687</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6thp" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 10:31, 26 February 2020
Neprilysin in complex with the inhibitor (R)-4-(1-carboxy-3-(3'-chlorobiphenyl-4-yl)propan-2-ylamino)-4-oxobutanoic acid
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