TY - JOUR
T1 - A hybrid platform featuring nanomagnetic ligand fishing for discovering COX-2 selective inhibitors from aerial part of Saussurea laniceps Hand.-Mazz
AU - Chen, Qilei
AU - Zhu, Lin
AU - Yip, Ka Man
AU - Tang, Yancheng
AU - Liu, Yi
AU - Jiang, Tao
AU - Zhang, Jianye
AU - Zhao, Zhongzhen
AU - Yi, Tao
AU - Chen, Hubiao
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China ( 81673691 , 82074123 , U1903126 ); the Health and Medical Research Fund in Hong Kong ( 16170251 ); Faculty Research Grant of Hong Kong Baptist University ( FRG2/17–18/080 ); the Guangdong Natural Science Foundation ( 2016A030313008 ); and the Applied Basic Research Program of Sichuan Province ( 2018JY0445 and 2019YJ0303 ).
PY - 2021/5/10
Y1 - 2021/5/10
N2 - Ethnopharmacological relevance: Saussurea laniceps Hand.-Mazz. (Compositae) is a representative “snow lotus” herb well known in Chinese folk medicine to treat inflammation-related diseases such as arthritis. S. laniceps (SL) shows anti-inflammatory and analgesic potencies and contains various constituents potentially with cyclooxygenase-2 (COX-2) selective inhibition. The herb is a valuable source of natural alternatives to synthetic COX-2 selective nonsteroidal anti-inflammatory drugs, a common medication for rheumatoid arthritis (RA) and osteoarthritis (OA) reported with serious cardiovascular side effects. Aim of the study: Based on an innovative drug screening platform, this study aimed to discover safe, effective COX-2 selective inhibitors from SL. Materials and methods: An enzyme-anchored nanomagnetic fishing assay was developed to separate COX-2 ligands from SL. Cell and animal models of cardiomyocytes, lipopolysaccharide-stimulated macrophages, rat adjuvant-induced arthritis, and anterior cruciate ligament transection-induced OA rats, were adopted to screen the single/combined ligands regarding toxicity and bioactivity levels. Molecular docking was employed to unravel binding mechanisms of the ligands towards COX-1 and COX-2. Results: Four COX-2 selective compounds were separated from SL using optimized COX-2-functionalized magnetic nanoparticles. All the four ligands were proved with evidently lower cardiotoxicity both in vitro and in vivo than celecoxib, a known COX-2 selective inhibitor. Two ligands, scopoletin and syringin, exhibited potent anti-arthritic activities in rat models of RA and OA by alleviating clinical statuses, immune responses, and joint pathological features; their optimum combination ratio was discovered with stronger remedial effects on rat OA than single administrations. The COX-1/2 binding modes of the two phytochemicals contributed to explain their cardiac safety and therapeutic performances. Conclusions: The screened chemicals are promising to be developed as COX-2 selective inhibitors as part of treating RA and OA. The hybrid strategy for discovering therapeutic agents from SL is shown here to be efficient; it should be equally valuable for finding other active chemicals in other natural sources.
AB - Ethnopharmacological relevance: Saussurea laniceps Hand.-Mazz. (Compositae) is a representative “snow lotus” herb well known in Chinese folk medicine to treat inflammation-related diseases such as arthritis. S. laniceps (SL) shows anti-inflammatory and analgesic potencies and contains various constituents potentially with cyclooxygenase-2 (COX-2) selective inhibition. The herb is a valuable source of natural alternatives to synthetic COX-2 selective nonsteroidal anti-inflammatory drugs, a common medication for rheumatoid arthritis (RA) and osteoarthritis (OA) reported with serious cardiovascular side effects. Aim of the study: Based on an innovative drug screening platform, this study aimed to discover safe, effective COX-2 selective inhibitors from SL. Materials and methods: An enzyme-anchored nanomagnetic fishing assay was developed to separate COX-2 ligands from SL. Cell and animal models of cardiomyocytes, lipopolysaccharide-stimulated macrophages, rat adjuvant-induced arthritis, and anterior cruciate ligament transection-induced OA rats, were adopted to screen the single/combined ligands regarding toxicity and bioactivity levels. Molecular docking was employed to unravel binding mechanisms of the ligands towards COX-1 and COX-2. Results: Four COX-2 selective compounds were separated from SL using optimized COX-2-functionalized magnetic nanoparticles. All the four ligands were proved with evidently lower cardiotoxicity both in vitro and in vivo than celecoxib, a known COX-2 selective inhibitor. Two ligands, scopoletin and syringin, exhibited potent anti-arthritic activities in rat models of RA and OA by alleviating clinical statuses, immune responses, and joint pathological features; their optimum combination ratio was discovered with stronger remedial effects on rat OA than single administrations. The COX-1/2 binding modes of the two phytochemicals contributed to explain their cardiac safety and therapeutic performances. Conclusions: The screened chemicals are promising to be developed as COX-2 selective inhibitors as part of treating RA and OA. The hybrid strategy for discovering therapeutic agents from SL is shown here to be efficient; it should be equally valuable for finding other active chemicals in other natural sources.
KW - Arthritis
KW - Celecoxib (PubChem CID: 2662)
KW - Chlorogenic acid (PubChem CID: 1794427)
KW - Cyclooxygenase-2
KW - Drug discovery
KW - Ligand fishing
KW - Magnetic nanoparticles
KW - Saussurea laniceps
KW - Scopoletin (PubChem CID: 5280460)
KW - Syringin (PubChem CID: 5316860)
KW - Umbelliferone (PubChem CID: 5281426)
UR - http://www.scopus.com/inward/record.url?scp=85100416431&partnerID=8YFLogxK
U2 - 10.1016/j.jep.2021.113849
DO - 10.1016/j.jep.2021.113849
M3 - Journal article
C2 - 33485983
AN - SCOPUS:85100416431
SN - 0378-8741
VL - 271
JO - Journal of Ethnopharmacology
JF - Journal of Ethnopharmacology
M1 - 113849
ER -
