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Aliskiren displays long-lasting interactions with human renin
Thomas Gossas1, Lotta Vrang, Ian Henderson
1Department of Biochemistry and Organic Chemistry, BMC, Uppsala University, Box 576, 75123 Uppsala, Sweden.
Naunyn-Schmiedeberg'S Archives of Pharmacology
|December 24, 2011
Summary
Aliskiren, a hypertension drug, shows a long-lasting interaction with renin. This prolonged binding may explain its extended efficacy beyond its half-life.
Area of Science:
- Pharmacology
- Biochemistry
- Cardiovascular Medicine
Background:
- Aliskiren is a selective renin inhibitor used for hypertension.
- Its observed efficacy duration exceeds predictions based on its circulating half-life.
Purpose of the Study:
- To characterize the kinetics of the aliskiren-renin interaction.
- To compare aliskiren's binding kinetics with other renin inhibitors.
Main Methods:
- Assessed inhibition of recombinant human renin using fluorescent substrate cleavage.
- Monitored human plasma renin activity (PRA) by measuring angiotensin I generation.
- Determined binding kinetics (association and dissociation rates) using surface plasmon resonance (SPR).
Main Results:
- Aliskiren and remikiren were equipotent inhibitors of recombinant renin (K(i) ≤ 0.04 nM).
- Both drugs potently inhibited PRA (IC₅₀ values of 0.2-0.3 nM).
- Aliskiren exhibited a long residence time with renin (2.5 hours), significantly longer than compound 1 (3 minutes).
Conclusions:
- The prolonged interaction between aliskiren and human renin likely contributes to its 24-hour antihypertensive effect.
- This sustained binding may also influence target-mediated drug disposition.
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