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    Home > Two pronged approach: Lu Hua group, School of chemistry and molecular engineering, Peking University, combined macrocyclization and polyamino acid coupling strategies to greatly improve the pharmaceutical activity of protein in vivo

    Two pronged approach: Lu Hua group, School of chemistry and molecular engineering, Peking University, combined macrocyclization and polyamino acid coupling strategies to greatly improve the pharmaceutical activity of protein in vivo

    • Last Update: 2018-01-24
    • Source: Internet
    • Author: User
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    Protein is a kind of important clinical medicine, but its pharmacognosy performance is limited by its poor stability, short half-life in vivo and high defect of autoimmunity Cyclization of peptides / proteins is a common method to enhance the activity and stability of peptides / proteins in vitro In addition, because of its limited configuration and small molecular size, cyclic peptides have better tissue permeability than linear peptides However, due to the lack of necessary "stealth" mechanism, the cycle time of cyclized peptides and proteins in vivo is relatively short, and most of the studies stay at the cell level, and there are few systematic reports on Pharmacognosy in vivo Polymer coupling is a common method to prolong the circulation time of protein drugs in vivo However, due to its large steric hindrance effect, the protein activity of protein polymer conjugates is often greatly reduced, and the tissue permeability is poor Lu Hua group, School of chemistry and molecular engineering, Peking University, prepared protein poly amino acid macrocyclic conjugate by combining cyclization and polymer coupling, and obtained excellent pharmacognosy effect (Figure 1) Fig 1 the protein poly amino acid macromolecular coupling compound can have the advantages of two strategies of cyclization and macromolecular coupling at the same time, thus reflecting more excellent pharmaceutical activity Source: site specific protein poly amino acid coupling technology developed by school of chemistry and molecular engineering of Peking University Based on the laboratory (j.am.chem.soc 2016, 138, 10995 − 11000), using interferon - α 2B (an antiviral and anti-tumor drug) as a model drug protein, the researchers synthesized the head tail interferon poly amino acid macrocyclic conjugate, and compared it with wild-type interferon, two linear interferon poly amino acid conjugates, and one linear interferon peg conjugates (Fig 2) The results showed that the pharmaceutical properties of ifn-paa macrocyclic conjugates were better than those of other control groups in both cell and animal experiments Most particularly, macrocyclic conjugates not only have the typical advantages of traditional protein polymer conjugates, such as long cycle time and high tumor retention, but also have the unique high tumor permeability of cyclic peptide drugs (Fig 2) Because of these excellent properties, ifn-paa macrocyclic conjugates showed excellent antitumor activity in many animal models, and their antitumor effect was significantly better than that of the experimental control group (including wild-type IFN, PEG conjugates and linear poly amino acid conjugates) In this study, the in vivo pharmaceutical properties of protein poly amino acid macrocyclic conjugates were discussed in detail, which provided a new way for people to design the next generation of protein / peptide drugs The ifn-paa macrocyclic conjugates reported in this paper have broad application prospects and considerable transformation potential The expected indications include ovarian cancer, prostate cancer, skin lymphoma, melanoma and many other malignant tumors At the same time, they also have certain potential for viral diseases such as hepatitis B and hepatitis C The work was recently published online in the Journal of the American social Fig 2 Ifn-paa macrocyclic conjugates have the characteristics of tumor retention, deep tissue penetration and good antitumor activity Source: Hou Yingqin, Ph.D student, School of chemistry and molecular engineering, Peking University, and Zhou Yu, master's student in joint training, are the co first authors of this paper, and researcher LV Hua is the corresponding author This work was supported by the national key R & D plan nano project (2016yfa0201400) and the National Natural Science Foundation of China (21722401, 2147404, and 21434008) Paper link: http://pubs.acs.org/doi/10.1021/jacs.7b13017 profile of researcher LV Hua: http:// researcher LV Hua
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