Design and development of a peptide-based adiponectin receptor agonist for cancer treatment.
Design and development of a peptide-based adiponectin receptor agonist for cancer treatment.
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DOI：
10.1186/1472-6750-11-90
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发表时间：
2011-10-05
影响因子：
3.5
通讯作者：
Surmacz E
中科院分区：
文献类型：
--
作者：
Otvos L Jr;Haspinger E;La Russa F;Maspero F;Graziano P;Kovalszky I;Lovas S;Nama K;Hoffmann R;Knappe D;Cassone M;Wade J;Surmacz E
脂联素是一种脂肪组织来源的脂肪因子，对胰岛素抵抗、心血管疾病、炎症和癌症具有有益作用。肥胖个体的循环脂联素水平降低，这一特征与发展几种代谢性、免疫性和肿瘤性疾病的风险增加相关。因此，脂联素的药理学替代可能被证明是临床有益的，特别是对于肥胖患者人群。目前，脂联素为基础的治疗是不可用的，部分原因是还不清楚的结构/功能的关系的细胞因子和困难的全尺寸脂联素蛋白转化为一个可行的药物。我们的目的是产生脂联素为基础的短肽，可以模拟脂联素的作用，并适合作为癌症治疗的临床前和临床开发。使用一组覆盖整个脂联素球状结构域（残基105-254）的66个重叠的10个氨基酸长的肽，我们鉴定了149-166区域为脂联素活性位点。活性位点的三维建模和覆盖该区域的另外330种肽类似物的功能筛选导致开发了前导肽模拟物ADP 355（H-DAsn-Ile-Pro-Nva-Leu-Tyr-DSer-Phe-Ala-DSer-NH 2）。在几种脂联素受体阳性癌细胞系中，ADP 355在100 nM-10 μM浓度下以剂量依赖性方式限制增殖（超过50 ng/mL球状脂联素的作用）。此外，ADP 355以脂联素样方式调节几个关键信号通路（AMPK、Akt、STAT 3、ERK 1/2）。siRNA敲除实验表明，ADP 355的作用可以通过两种脂联素受体传递，其中AdipoR 1的作用更大。在体内，1 mg/kg/天ADP 355腹腔内给药28天可抑制原位人乳腺癌异种移植物的生长约31%。该肽在小鼠血液或血清中显示出优异的稳定性（至少30分钟），并且在正常CBA/J小鼠中在5-50 mg/kg推注剂量下不诱导总体毒性作用。ADP 355是一种一流的脂联素受体激动剂。其生物活性、在生物液体中的上级稳定性以及可接受的毒性特征表明，该肽模拟物代表了用于药物开发的真正的先导化合物，以替代癌症和其它恶性肿瘤中的低脂联素水平。
Adiponectin, a fat tissue-derived adipokine, exhibits beneficial effects against insulin resistance, cardiovascular disease, inflammatory conditions, and cancer. Circulating adiponectin levels are decreased in obese individuals, and this feature correlates with increased risk of developing several metabolic, immunological and neoplastic diseases. Thus, pharmacological replacement of adiponectin might prove clinically beneficial, especially for the obese patient population. At present, adiponectin-based therapeutics are not available, partly due to yet unclear structure/function relationships of the cytokine and difficulties in converting the full size adiponectin protein into a viable drug. We aimed to generate adiponectin-based short peptide that can mimic adiponectin action and be suitable for preclinical and clinical development as a cancer therapeutic. Using a panel of 66 overlapping 10 amino acid-long peptides covering the entire adiponectin globular domain (residues 105-254), we identified the 149-166 region as the adiponectin active site. Three-dimensional modeling of the active site and functional screening of additional 330 peptide analogs covering this region resulted in the development of a lead peptidomimetic, ADP 355 (H-DAsn-Ile-Pro-Nva-Leu-Tyr-DSer-Phe-Ala-DSer-NH2). In several adiponectin receptor-positive cancer cell lines, ADP 355 restricted proliferation in a dose-dependent manner at 100 nM-10 μM concentrations (exceeding the effects of 50 ng/mL globular adiponectin). Furthermore, ADP 355 modulated several key signaling pathways (AMPK, Akt, STAT3, ERK1/2) in an adiponectin-like manner. siRNA knockdown experiments suggested that ADP 355 effects can be transmitted through both adiponectin receptors, with a greater contribution of AdipoR1. In vivo, intraperitoneal administration of 1 mg/kg/day ADP 355 for 28 days suppressed the growth of orthotopic human breast cancer xenografts by ~31%. The peptide displayed excellent stability (at least 30 min) in mouse blood or serum and did not induce gross toxic effects at 5-50 mg/kg bolus doses in normal CBA/J mice. ADP 355 is a first-in-class adiponectin receptor agonist. Its biological activity, superior stability in biological fluids as well as acceptable toxicity profile indicate that the peptidomimetic represents a true lead compound for pharmaceutical development to replace low adiponectin levels in cancer and other malignancies.
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影响因子：
4.6
作者：
Fenton, Jenifer I.;Birmingham, Janette M.
通讯作者：
Birmingham, Janette M.
影响因子：
3.9
作者：
Fang, X.;Sweeney, G.
通讯作者：
Sweeney, G.
DOI：
10.1016/j.bbrc.2006.04.076
发表时间：
2006-06-23
影响因子：
3.1
作者：
Dieudonne, Marie-Noelle;Bussiere, Marianne;Pecquery, Rene
通讯作者：
Pecquery, Rene
影响因子：
4
作者：
Akifusa, Sumio;Kamio, Noriaki;Yamashita, Yoshihisa
通讯作者：
Yamashita, Yoshihisa
影响因子：
2.2
作者：
Arditi, J. D.;Venihaki, M.;Chrousos, G. P.
通讯作者：
Chrousos, G. P.