Yu Yongsheng, associate researcher, Tongji University and Xia Jiang, associate professor, Chinese University of Hong Kong

Syntenin, a multi domain adaptor protein, regulates the invasion and migration of tumor cells through its pdz1 and pdz2 domains Previous syntenin inhibitors had weak affinity and no specificity, which seriously affected their further application Recently, Yu Yongsheng, associate researcher of Tongji University, and Xia Jiang, associate professor of the Chinese University of Hong Kong, worked together to report for the first time the design, synthesis and screening optimization of peptide inhibitors based on syntenin natural epitopes, which showed high affinity (EUR J Med Chem 2018, 154, 354-366) Yu Yongsheng, Ph.D., associate researcher of Tongji University, master tutor In 2011, he received a master's degree in medicine from the Second Military Medical University of the people's Liberation Army and a doctor's degree in chemistry from the Chinese University of Hong Kong in 2015 From 2015 to 2017, he was engaged in post doctoral research at the Chinese University of Hong Kong Now, he is a deputy researcher of the first maternal and child health care institute affiliated to Tongji University and the higher Research Institute of Tongji University In 2018, he was selected into Shanghai Pujiang talent plan (Class A) Mainly engaged in tumor targeted therapy and peptide inhibitors Prof Xia Jiang, Ph.D., associate professor, doctoral supervisor, Chinese University of Hong Kong He received his Bachelor of science from Nanjing University in 1999 and his doctor's degree from Stanford University in 2006 From 2007 to 2008, he was engaged in postdoctoral research at Caltech and Howard Hughes Institute of medicine Since 2009, he has successively served as assistant professor and associate professor of the Chinese University of Hong Kong Mainly engaged in the research of protein chemistry and chemical biology Cutting edge scientific research achievements: antineoplastic research of syntenin targeted peptide inhibitors syntenin regulates the invasion and migration of tumor cells through its pdz1 and pdz2 domains, so syntenin can be an effective tumor inhibition target However, due to the hybrid binding between PDZ protein and its natural ligands and the weak binding power, the research and development of PDZ protein inhibitors are seriously affected Two strategies were used to design and optimize syntenin high affinity inhibitors: 1 Dimerization of syntenin natural epitopes and peptides; 2 Introduction of unnatural amino acids into peptide inhibitors Firstly, four peptide epitopes rvafeel, tnefya, dkeyyv and ledsvf of syntenin natural binding protein were selected Fluorescence polarization (FP) was used to detect the affinity of each peptide segment with syntenin two PDZ domains (Fig 1) The results showed that the affinity was generally weak Fig 1 Affinity detection of polypeptide and pdz1 / pdz2 domain (source: EUR J Med Chem.) then, the researchers obtained different dimers 2-2 to 4-4 by solid-phase synthesis in different combinations (Fig 2) At this time, the affinity of dimer peptide 3-3 with syntenin tandem PDZ protein can be increased to 0.8 μ M Figure 2 Dimer structure and affinity identification of different epitope peptide segments (source: EUR J Med Chem.), in order to further enhance the affinity, the researcher selected dimer 3-3 as the optimization object, and replaced the amino acids of P1 and P2 on the single chain of dimer peptide with the non natural amino acid naphylalanine (φ), so as to enhance the hydrophobicity of dimer , which in turn increases affinity (Figure 3) Fig 3 The optimized FP detection results of different polypeptide structures and their affinity with PDZ, pdz1 and pdz2 (source: EUR J Med Chem.) showed that the affinity of dimer 13-13 with syntenin protein of PDZ in series reached 210 nm Then, the researchers connected the transmembrane peptide to 13-13, and further tested its antitumor effect in cervical cancer cell HeLa with high syntenin expression, breast cancer cell MDA-MB-435 and breast cancer cell MDA-MB-231 with low expression Fig 4 The results of cell experiments on the membrane penetrating efficiency of dimer 13-13 polypeptide (source: EUR J Med Chem.) by confocal microscopy confirmed that the dimer connected with membrane penetrating peptide can enter the cell efficiently (Fig 4), and inhibit the invasion and metastasis of HeLa and MDA-MB-435 tumor cells with high syntenin expression, but it can inhibit the low expression of MDA-MB-231 The inhibition effect of cells was not significant All of these fully confirmed the syntenin specificity of dimer inhibitors, which is of great significance for the preclinical development of targeted peptide drugs The research results have been published in EUR J Med Chem (EUR J Med Chem 2018, 154, 354-366) Dr Liu Jiahui is the first author of the paper, and Yu Yongsheng, associate researcher, and Xia Jiang, associate professor, are the corresponding authors Nowadays, people and scientific research have been paid more and more attention in the economic life China has ushered in the "node of science and technology explosion" Behind the progress of science and technology is the work of countless scientists In the field of chemistry, in the context of the pursuit of innovation driven, international cooperation has been strengthened, the influence of Returned Scholars in the field of R & D has become increasingly prominent, and many excellent research groups have emerged in China For this reason, CBG information adopts the 1 + X reporting mechanism CBG information, chembeangoapp, chembeango official microblog, CBG wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the domestic representative research group, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.