| Budget Amount *help |
¥3,150,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥150,000)
Fiscal Year 2007: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
This research project focuses on the synthesis of novel retro-inverso peptide analogues, which have selective angiotensin-l-converting enzyme (ACE) inhibition. ACE raises blood pressure by converting angiotensin I (Ang I), decapeptide, into the potent vasoconstrictor angiotensin II (Ang II), octapeptide. ACE also egradates sodilative bradykinin (BK) in blood vessels. ACE inhbitors such as captopril inhbit both the conversion of Mg I and the degradation of BK that may cause several side effects in human body. We have noticed the selective ACE inhbition by peptides, which inhibit Ang I conversion but show no effect on BK degradation. The goal of this project is to offer an anti-hypertensive retro-inverso peptidyl product for medicinal use with no side effect by BK.
Some peptides Val Ala-Trp, Val-Ser-Trp and Ala-Trp, which have isolated irom enzymatic hydrolysates of human proteins, show selective ACE inhbition with little effect on BK degradation. The Ki ratio of these peptides were measu
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red 28, 22 and 64, respectively. On the other hand, that of ACE inhbitory peptides was measured below 10. Both C-terminal Tip residue and C-terminal carboxyl moiety needed to show selective inhibitory activity in comparison with other ACE inhibitory peptides.
Retro-inverso peptides consist of all D-amino adds with reversed direction. The side chains of these structures are thought same stereo-chemical position as those of normal peptides with L-amino adds. In addition, the retro-inverso peptides are thought resistant to the attack of proteolytic enzymes in human body.
We have synthesized a building unit m_dTrp-OtBu, t-butyl 2 (indol-3-y1)methyl malonate, to change amino moiety of Tip residue to carboxyl moiety. Using this unit we have synthesed m_d Trp-_dAla-_dVal-NH_2, retro-inverso peptidyl analogue with carboxyl moiety at the N-terminus. Although the inhibitional activity of this peptide analogue was not so potent, it was found to clearly inh bit Mg I conversion but not to inhibit BK degradation. Less
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