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首页> 外文期刊>BMC Biotechnology >Design and development of a peptide-based adiponectin receptor agonist for cancer treatment
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Design and development of a peptide-based adiponectin receptor agonist for cancer treatment

机译：基于肽的脂联素受体激动剂用于癌症治疗的设计和开发

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Background 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. Results 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- D Asn-Ile-Pro-Nva-Leu-Tyr- D Ser-Phe-Ala- D Ser-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. Conclusions 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.
机译：背景技术脂连蛋白是脂肪组织衍生的脂肪因子，对胰岛素抵抗，心血管疾病，炎症和癌症表现出有益的作用。肥胖个体的循环脂联素水平降低，并且该特征与发生几种代谢，免疫和肿瘤疾病的风险增加相关。因此，脂联素的药理替代可能在临床上证明是有益的，尤其是对于肥胖的患者人群。目前，基于脂连蛋白的疗法尚不可用，部分原因是细胞因子的结构/功能关系尚不清楚，并且难以将全尺寸脂连蛋白转化为可行药物。结果我们的目标是产生一种基于脂联素的短肽，该肽可模仿脂联素的作用，适合作为癌症治疗剂进行临床前和临床开发。使用一组覆盖整个脂连蛋白球状结构域（残基105-254）的66个重叠的10个氨基酸长的肽，我们将149-166区确定为脂联素活性位点。活性位点的三维建模和覆盖该区域的其他330种肽类似物的功能筛选导致了拟肽模拟物ADP 355（H- D Asn-Ile-Pro-Nva-Leu-Tyr-D Ser-Phe -Ala- D Ser-NH 2 ）。在几种脂联素受体阳性癌细胞系中，ADP 355在100 nM-10μM浓度下（剂量超过50 ng / mL球状脂联素的作用）以剂量依赖性方式限制了增殖。此外，ADP 355以脂联素样方式调节了几个关键的信号通路（AMPK，Akt，STAT3，ERK1 / 2）。 siRNA敲低实验表明，ADP 355的作用可以通过两个脂联素受体传递，而AdipoR1的贡献更大。在体内，腹膜内给予1 mg / kg / day ADP 355 28天可抑制原位人类乳腺癌异种移植的生长，约31％。该肽在小鼠血液或血清中显示出极好的稳定性（至少30分钟），并且在正常CBA / J小鼠中以5-50 mg / kg推注剂量不产生总毒性作用。结论ADP 355是一流的脂联素受体激动剂。它的生物活性，在生物液体中的优异稳定性以及可接受的毒性特征表明，拟肽代表了一种真正的药物开发先导化合物，可替代癌症和其他恶性肿瘤中低脂联素水平。

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