A kisspeptin-10 analog with greater in vivo bioactivity than kisspeptin-10.
A kisspeptin-10 analog with greater in vivo bioactivity than kisspeptin-10.
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DOI：
10.1152/ajpendo.00426.2009
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发表时间：
2010-02
期刊：
影响因子：
--
通讯作者：
Murphy KG
中科院分区：
文献类型：
--
作者：
Curtis AE;Cooke JH;Baxter JE;Parkinson JR;Bataveljic A;Ghatei MA;Bloom SR;Murphy KG
kisspeptins是刺激下丘脑-垂体-性腺（HPG）轴的神经肽。最小的内源性kisspeptin，kisspeptin-10（KP-10），与受体KISS 1 R结合的亲和力与全长肽kisspeptin-54（KP-54）相似，但在体内的有效性较低，可能是因为酶分解或清除增加。kisspeptin系统可能在治疗生殖疾病和内分泌癌方面具有治疗潜力。我们对KP-10的结构进行了合理的修饰，并测试了这些类似物对KISS 1 R的结合亲和力。测试以相对高的亲和力结合KISS 1 R的那些类似物在体外刺激ERK 1/2磷酸化的能力和它们在体内刺激HPG轴的能力。一种类似物[dY] 1 KP-10与KISS 1 R结合，与KP-10的亲和力较低，并在体外表现出相似的生物活性。然而，在体内外周给药[dY] 1 KP-10增加血浆LH和睾酮更有力地比KP-10本身在20分钟后注射小鼠。此外，注射后60分钟，0.15 nmol [dY] 1 KP-10显著增加小鼠的总睾酮水平，而相同剂量的KP-10没有显著影响。如果kisspeptin/KISS 1 R信号系统的操作证明在治疗上有用，那么持久的类似物如[dY] 1 KP-10可能比内源性形式的kisspeptin具有更大的治疗潜力。
The kisspeptins are neuropeptides that stimulate the hypothalamo-pituitary-gonadal (HPG) axis. The smallest endogenous kisspeptin, kisspeptin-10 (KP-10), binds to the receptor KISS1R with a similar affinity to the full-length peptide, kisspeptin-54 (KP-54), but is less effective in vivo, possibly because of increased enzymatic breakdown or clearance. The kisspeptin system may have therapeutic potential in the treatment of reproductive disorders and endocrine cancers. We have rationally modified the structure of KP-10 and tested the binding affinity of these analogs for the KISS1R. Those analogs that bound with relatively high affinity to KISS1R were tested for ability to stimulate ERK1/2 phosphorylation in vitro and for their ability to stimulate the HPG axis in vivo. One analog, [dY]1KP-10, bound to KISS1R with lower affinity to KP-10 and exhibited similar bioactivity in vitro. However, in vivo peripheral administration of [dY]1KP-10 increased plasma LH and testosterone more potently than KP-10 itself at 20 min postinjection in mice. In addition, 60 min postinjection, 0.15 nmol [dY]1KP-10 significantly increased total testosterone levels in mice whereas the same dose of KP-10 had no significant effect. Should manipulation of the kisspeptin/KISS1R signaling system prove therapeutically useful, long-lasting analogs such as [dY]1KP-10 may have greater therapeutic potential than endogenous forms of kisspeptin.
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DOI：
10.1073/pnas.1834399100
发表时间：
2003-09-16
影响因子：
11.1
作者：
de Roux, N;Genin, E;Milgrom, E
通讯作者：
Milgrom, E
影响因子：
4.8
作者：
Muir, AI;Chamberlain, L;Harrison, DC
通讯作者：
Harrison, DC
影响因子：
4
作者：
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通讯作者：
Miele, ME
DOI：
10.1073/pnas.0409822102
发表时间：
2005-02-08
影响因子：
11.1
作者：
Shahab, M;Mastronardi, C;Plant, TM
通讯作者：
Plant, TM
影响因子：
7.3
作者：
Orsini, Michael J.;Klein, Mark A.;Mayo, Kevin H.
通讯作者：
Mayo, Kevin H.