Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy.
Institut National de la Santé et de la Recherche Médicale Centre de Recherche des Cordeliers Sorbonne Université, Université de Paris, 75006 Paris, France.
Biomolecules. 2021 Feb 25;11(3):351. doi: 10.3390/biom11030351.
The ability to regulate the recruitment of immune cells makes chemokines and their receptors attractive drug targets in many inflammatory diseases. Based on its preferential expression on T helper type 2 (Th2) cells, C-C chemokine receptor type 4 (CCR4) has been widely studied in the context of allergic diseases, but recent evidence on the expression of CCR4 in other cell types has considerably expanded the potential applications of CCR4 antagonism. However, the current number of approved indications, as well as the portfolio of CCR4-targeting drugs, are still limited. In the present study, we have assessed the potential therapeutic efficacy of a CCR4 small molecule antagonist, SP50, discovered via an in silico-based approach, against a variety of pre-clinical settings of infection with the fungus . We show that SP50 efficiently worked as prophylactic vaccine adjuvant in immunocompetent mice, protected against invasive aspergillosis in immunosuppressed mice. Further, the CCR4 antagonist prevented allergic bronchopulmonary aspergillosis in susceptible mice, and in a murine model of cystic fibrosis, a genetic disorder characterized by chronic pulmonary inflammation and recurrent infections. In conclusion, our results extend the potential applications of CCR4 antagonism and prompt for the development of novel compounds with the potential to progress to clinical trials.
趋化因子及其受体能够调节免疫细胞的募集，这使得它们成为许多炎症性疾病中极具吸引力的药物靶点。CC 趋化因子受体 4（CCR4）在 Th2 细胞上的优先表达使其在过敏疾病的背景下得到了广泛研究，但 CCR4 在其他细胞类型中的表达的最新证据大大扩展了 CCR4 拮抗作用的潜在应用。然而，目前获得批准的适应症数量以及 CCR4 靶向药物的组合仍然有限。在本研究中，我们评估了一种通过基于计算的方法发现的 CCR4 小分子拮抗剂 SP50 在多种真菌感染的临床前模型中的潜在治疗效果。我们发现 SP50 可作为免疫功能正常的小鼠的预防性疫苗佐剂，在免疫抑制的小鼠中可预防侵袭性曲霉病。此外，该 CCR4 拮抗剂可预防易感小鼠的变应性支气管肺曲霉病，以及囊性纤维化（一种以慢性肺部炎症和反复感染为特征的遗传性疾病）的小鼠模型。总之，我们的研究结果扩展了 CCR4 拮抗作用的潜在应用，并提示开发具有潜在临床试验进展的新型化合物的必要性。
