Abstract
Hypertension is currently one of the most serious health issues worldwide. Nicotianamine, a non-peptide-type amino acid trimer, is ubiquitously present in higher plants and plays a role as an internal metal transporter. It is known that nicotianamine inhibits ACE activity and that oral treatment with the compound improves hypertension. However the mode of action remains unclear, due to lack of crystallographic data. Although a structure-activity relationship study of nicotianamine has the potential to uncover the details of the inhibition profile, the azetidine-2-carboxylic acid moiety in nicotianamine has become a critical barrier for further biochemical research due to limited commercial supply and difficulties with structural modification. In this paper, ten nicotianamine analogs without azetidine-2-carboxylic acid moiety were prepared and their inhibition of angiotensin I-converting enzyme was investigated. Among these analogs, a phenylalanine analog, (2S,3′S,3″S)-N-{3′-(3″-amino-3″-carboxypropylamino)-3′-carboxypropyl}phenylalanine, displayed the most potent activity. The inhibition activity of the compound corresponded to that of captopril. These results suggested a possibility of structural modification of nicotianamie to develop antihypertensive drugs. Molecular docking studies with Gold were also performed to predict the binding poses of nicotianamine and its analog, suggesting that nicotianamine and its analogs combine a plausible allosteric site in an area away from the catalytic site in ACE.
Highlights
Hypertension is currently one of the most serious health issues worldwide
The inhibition pattern of captopril is verified to be competitive, and the binding features of captopril with Angiotensin I-converting enzyme (ACE) have been well-established by X-ray crystallographic studies [4], thereby leading to the development of other antihypertensive drugs [5], such as enalapril, that bind to ACE in a similar manner
Determining whether the trimeric structure and the azetidine-2-carboxylic acid moiety are essential for ACE inhibitors (ACEIs) activity would help define the mode of action of nicotianamine and aid in the development of a new type of hypertensive drug
Summary
Renin-angiotensin system (RAS) is involved in the long-term regulation of blood pressure and volume in the human body and is considered to be one of the key targets for hypertension drugs. Many ACE inhibitors (ACEIs) such as captopril [1,2,3] have been developed and are being used in hypertension therapy (Figure 1). The inhibition pattern of captopril is verified to be competitive, and the binding features of captopril with ACE have been well-established by X-ray crystallographic studies [4], thereby leading to the development of other antihypertensive drugs [5], such as enalapril, that bind to ACE in a similar manner. Nicotianamine inhibits ACE activity, and oral treatment with the compound improves hypertension in both spontaneously hypertensive rats (SHR) and Tsukuba hypertensive mice (THM) [10,11,12]
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