Targeting the PDGF-B/PDGFR-β Interface with Destruxin A5 to Selectively Block PDGF-BB/PDGFR-ββ Signaling and Attenuate Liver Fibrosis.
PDGF-BB/PDGFR-ββ signaling plays very crucial roles in the process of many diseases such as liver fibrosis. However, drug candidates with selective affinities for PDGF-B/PDGFR-β remain deficient. Here, we identified a natural cyclopeptide termed destruxin A5 that effectively inhibits PDGF-BB-induced PDGFR-β signaling. Interestingly and importantly, the inhibitory mechanism is distinct from the mechanism of tyrosine kinase inhibitors because destruxin A5 does not have the ability to bind to the ATP-binding pocket of PDGFR-β. Using Biacore T200 technology, thermal shift technology, microscale thermophoresis technology and computational analysis, we confirmed that destruxin A5 selectively targets the PDGF-B/PDGFR-β interaction interface to block this signaling. Additionally, the inhibitory effect of destruxin A5 on PDGF-BB/PDGFR-ββ signaling was verified using in vitro, ex vivo and in vivo models, in which the extent of liver fibrosis was effectively alleviated by destruxin A5. In summary, destruxin A5 may represent an efficacious and more selective inhibitor of PDGF-BB/PDGFR-ββ signaling.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China; Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, China.
Xingqi
X
Wang
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
Xuefeng
X
Wu
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
Aihua
A
Zhang
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
Shiyu
S
Wang
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
Chunhui
C
Hu
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
Wei
W
Chen
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
Yan
Y
Shen
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China. Electronic address: rxtan@nju.edu.cn.
Renxiang
R
Tan
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China. Electronic address: yangsun@nju.edu.cn.
Yang
Y
Sun
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China. Electronic address: molpharm@163.com.
Qiang
Q
Xu
D000818:Animals; D000077214:Becaplermin; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology / Q000379:methods; D004195:Disease Models, Animal; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D051381:Rats; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D010456:Peptides, Cyclic; D020574:Proto-Oncogene Proteins c-sis; C000614722:destruxin A5; D000077214:Becaplermin; D020797:Receptor, Platelet-Derived Growth Factor beta
Destruxin A5; Liver fibrosis; PDGF-B/PDGFR-β; Protein–protein interface; Selective inhibitor