Division of Biomedical Sciences, School of Medicine, University of California Riverside, 900 University Avenue, Riverside, California 92521, United States.
Magnetic Resonance Center (CERM), University of Florence and Consorzio Interuniversitario Risonanze Magnetiche di Metallo Proteine (CIRMMP), Via L. Sacconi 6, 50019 Sesto Fiorentino, Italy.
J Med Chem. 2020 Nov 12;63(21):12911-12920. doi: 10.1021/acs.jmedchem.0c01285. Epub 2020 Oct 27.
Chronic obstructive pulmonary disease (COPD) is a lung disorder characterized by progressive airflow obstruction associated with inflammation and emphysema, and it is currently one of the leading causes of death worldwide. Recent studies with genetically engineered mice reported that during pulmonary inflammation, basophil-derived interleukin-4 can act on lung-infiltrating monocytes causing aberrant expression of the matrix metalloproteinase-12 (MMP-12). MMP-12 activity in turn causes the destruction of alveolar walls leading to emphysema, making it potentially a valid target for pharmacological intervention. Using nuclear magnetic resonance (NMR)- and structure-based optimizations, the current study reports on the optimized novel, potent, and selective MMP-12 inhibitors with single-digit nanomolar affinity and efficacy. Using a murine model of elastase-induced emphysema we demonstrated that the most potent agents exhibited a significant decrease in emphysema-like pathology compared to vehicle-treated mice, thus suggesting that the reported agents may potentially be translated into novel therapeutics for the treatment of COPD.
慢性阻塞性肺疾病（COPD）是一种肺部疾病，其特征是气流阻塞进行性加重，伴有炎症和肺气肿，目前是全球主要死亡原因之一。最近利用基因工程小鼠进行的研究报告称，在肺部炎症期间，嗜碱性粒细胞衍生的白细胞介素-4 可以作用于肺浸润的单核细胞，导致基质金属蛋白酶-12（MMP-12）的异常表达。MMP-12 的活性反过来导致肺泡壁的破坏，导致肺气肿，使其成为潜在的药理学干预的有效靶点。本研究采用核磁共振（NMR）和基于结构的优化方法，报告了优化后的新型、强效、选择性 MMP-12 抑制剂，其亲和力和功效均达到纳摩尔级。利用弹性蛋白酶诱导的肺气肿小鼠模型，我们证明了最有效的药物与对照组相比，肺气肿样病变明显减少，这表明所报道的药物可能有可能转化为治疗 COPD 的新型治疗药物。
