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Structure‐Based Discovery of Angiotensin‐Converting Enzyme 2 (ACE2) Activators
Author(s) -
Prada Jose Antonio Hernandez,
Ostrov David A,
Katovich Michael J,
Raizada Mohan K
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1365-c
Subject(s) - in vivo , pharmacology , in vitro , renin–angiotensin system , chemistry , angiotensin ii , stimulation , angiotensin converting enzyme 2 , enzyme , basal (medicine) , endogeny , drug discovery , blood pressure , medicine , biochemistry , biology , covid-19 , disease , infectious disease (medical specialty) , microbiology and biotechnology , insulin
Evidence indicates that ACE2, a member of the renin‐angiotensin system (RAS), is critical in counterbalancing the adverse effects associated with a hyperactive RAS. This led us to hypothesize that stimulation of endogenous ACE2 activity is beneficial against hypertension. In this study we employed a novel drug discovery strategy to identify small molecules that enhance ACE2 activity. We analyzed the open and closed crystal structures of ACE2 and used virtual screening techniques to select compounds targeted to molecular surface sites remote from the active site. Functional testing was performed in a fluorogenic peptide assay. Two compounds targeted to the same surface site were found to enhance ACE2 activity 2‐fold in vitro in a dose‐dependent manner, while ACE activity was unaffected. A pilot study was subsequently initiated to determine the effect of the compounds on blood pressure (BP) in the spontaneous hypertensive rat (SHR). Chronic treatment at an infusion rate of 200 ng/Kg/min via osmotic minipumps for 28 days did not significantly affect basal BP. Acute administration of 10mg/Kg of compound to conscious SHRs, however, did produce a transient and robust fall in BP (100 mmHg). Collectively, these observations demonstrate that structure‐based screening is a valid and efficient approach for identifying lead compounds that could influence ACE2 activity in vitro and in vivo . Supported by grant NIH/HL56921.