Discovery of Small Molecule Activators of Chemokine Receptor CXCR4 That Improve Diabetic Wound Healing.
Discovery of Small Molecule Activators of Chemokine Receptor CXCR4 That Improve Diabetic Wound Healing.
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发现可改善糖尿病伤口愈合的趋化因子受体 CXCR4 小分子激活剂。
DOI：
10.3390/ijms23042196
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发表时间：
2022-02-16
影响因子：
5.6
通讯作者：
Liechty KW
中科院分区：
文献类型：
--
作者：
Xu J;Hu J;Idlett-Ali S;Zhang L;Caples K;Peddibhotla S;Reeves M;Zgheib C;Malany S;Liechty KW
糖尿病会产生慢性炎症状态，导致血管疾病的发展和伤口愈合受损。尽管糖尿病溃疡对个人和社会的影响已知，但有效改善愈合的治疗方法有限。基质细胞衍生因子 1α (SDF-1α) 是一种 CXC 趋化因子，通过激活 CXC 趋化因子受体 4 型 (CXCR4) 受体发挥作用，将造血细胞募集到组织损伤部位并促进组织修复。 SDF-1α 的表达在糖尿病伤口中减少，表明其可能导致伤口愈合受损，并将 CXCR4 受体作为治疗研究的靶点。我们开发了一种高通量 β-抑制蛋白招募测定法，并进行了构效关系 (SAR) 研究，以筛选可用作 CXCR4 激动剂的化合物。我们从研究中鉴定出 CXCR4 激动剂 UCUF-728，并进一步验证了其在糖尿病成纤维细胞中的体外活性。 UCUF-728 减少糖尿病成纤维细胞中血管生成和 I 型胶原蛋白生成的负调节因子 miRNA-15b 和 miRNA-29a 的过度表达。在体内，UCUF-728 使糖尿病小鼠的伤口闭合时间缩短了 36%，并增加了血管生成的证据。总之，这项工作证明了小分子 CXCR4 激动剂作为糖尿病病理伤口愈合新疗法的临床潜力。
Diabetes produces a chronic inflammatory state that contributes to the development of vascular disease and impaired wound healing. Despite the known individual and societal impacts of diabetic ulcers, there are limited therapies effective at improving healing. Stromal cell-derived factor 1α (SDF-1α) is a CXC chemokine that functions via activation of the CXC chemokine receptor type 4 (CXCR4) receptor to recruit hematopoietic cells to locations of tissue injury and promote tissue repair. The expression of SDF-1α is reduced in diabetic wounds, suggesting a potential contribution to wound healing impairment and presenting the CXCR4 receptor as a target for therapeutic investigations. We developed a high-throughput β-arrestin recruitment assay and conducted structure–activity relationship (SAR) studies to screen compounds for utility as CXCR4 agonists. We identified CXCR4 agonist UCUF-728 from our studies and further validated its activity in vitro in diabetic fibroblasts. UCUF-728 reduced overexpression of miRNA-15b and miRNA-29a, negative regulators of angiogenesis and type I collagen production, respectively, in diabetic fibroblasts. In vivo, UCUF-728 reduced the wound closure time by 36% and increased the evidence of angiogenesis in diabetic mice. Together, this work demonstrates the clinical potential of small molecule CXCR4 agonists as novel therapies for pathologic wound healing in diabetes.
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影响因子：
3.7
作者：
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通讯作者：
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通讯作者：
Liechty, Kenneth W.
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作者：
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通讯作者：
Phillips, MI