Novel Bifunctional Natriuretic Peptides as Potential Therapeutics
Novel Bifunctional Natriuretic Peptides as Potential Therapeutics
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DOI：
10.1074/jbc.m804538200
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发表时间：
2008-12-12
影响因子：
4.8
通讯作者：
Potter, Lincoln R.
中科院分区：
文献类型：
--
作者：
Dickey, Deborah M.;Burnett, John C., Jr.;Potter, Lincoln R.
合成心房利钠肽（卡培立肽）和B型利钠肽（BNP;奈西立肽）用于治疗充血性心力衰竭。然而，尽管有益的心脏卸载特性，肾灌注压的降低限制了它们的临床有效性。最近，CD-NP，一种由C型利钠肽（CNP）融合到Dendroaspis利钠肽（DNP）的C-末端尾部组成的嵌合肽，在犬中显示出比BNP更能增强肾小球滤过率。然而，尚未确定反应性增加的分子基础。在这里，我们表明DNP尾对CNP具有显著的影响，将其从利钠肽受体（NPR）-A的非激动剂转化为部分激动剂，同时保持激活NPR-B的能力。该效应对人受体具有特异性，因为由于CNP在该种属中的混杂性质，CD-NP仅是大鼠NPR-A的略好激活剂。有趣的是，单独的DNP尾对任何NPR都没有影响，即使它在体内是有效的。为了进一步增加CD-NP对NPR-A的效力，我们将CNP环内的两个不同三联体序列转化为其在BNP中的相应残基。两种变体都表现出对NPR-A的亲和力增加和完全激动剂活性，而一种变体与任何已知的NPR-A激活剂一样有效。与以前的报道相反，我们发现DNP结合利钠肽清除受体（NPR-C）。然而，没有嵌合肽以比内源性配体显著更高的亲和力结合NPR-C。我们认为，双功能嵌合肽代表了新一代的利钠肽治疗。
Synthetic atrial natriuretic peptide (carperitide) and B-type natriuretic peptide (BNP; nesiritide) are used to treat congestive heart failure. However, despite beneficial cardiac unloading properties, reductions in renal perfusion pressures limit their clinical effectiveness. Recently, CD-NP, a chimeric peptide composed of C-type natriuretic peptide (CNP) fused to the C-terminal tail of Dendroaspis natriuretic peptide (DNP), was shown to be more glomerular filtration rate-enhancing than BNP in dogs. However, the molecular basis for the increased responsiveness was not determined. Here, we show that the DNP tail has a striking effect on CNP, converting it from a non-agonist to a partial agonist of natriuretic peptide receptor (NPR)-A while maintaining the ability to activate NPR-B. This effect is specific for human receptors because CD-NP was only a slightly better activator of rat NPR-A due to the promiscuous nature of CNP in this species. Interesting, the DNP tail alone had no effect on any NPR even though it is effective in vivo. To further increase the potency of CD-NP for NPR-A, we converted two different triplet sequences within the CNP ring to their corresponding residues in BNP. Both variants demonstrated increased affinity and full agonist activity for NPR-A, whereas one was as potent as any NPR-A activator known. In contrast to a previous report, we found that DNP binds the natriuretic peptide clearance receptor (NPR-C). However, none of the chimeric peptides bound NPR-C with significantly higher affinity than endogenous ligands. We suggest that bifunctional chimeric peptides represent a new generation of natriuretic peptide therapeutics.