Cell . . . Tumor immunotherapy breakthrough: covalent protein drugs and effectiveness research platform.

Compared with non covalent small molecule targeted drugs, covalent small molecule drugs have many advantages in pharmacodynamics and pharmacokinetics [1].at present, more than 30% of small molecule drugs targeting enzymes in the market can achieve irreversible regulation through covalent binding [2].covalent protein drugs can overcome some limitations of small molecule covalent drugs, such as enhancing target specificity and reducing glomerular filtration rate, thus prolonging the half-life in vivo [3].in addition, compared with non covalent protein drugs, such as recombinant human Fc fusion protein and antibody drugs, covalent protein drugs have the advantages of low toxicity, small molecular weight and low production cost [4].however, the interaction between natural protein-protein ligands is basically non covalent binding, and the clinical application of covalent protein drugs is still blank.therefore, it is of great clinical significance to develop the technology and platform of covalent protein drugs.at present, the clinical application of tumor immunotherapy methods, including monoclonal antibody immune checkpoint inhibitors (anti PD1 antibody) and car-t cell therapy, have shown clinical application advantages, but their effectiveness and safety need to be improved.solid tumors have complex immunosuppressive microenvironment and heterogeneity, and the formation mechanism of tumor immunosuppressive microenvironment needs further elucidation.however, tumor immunotherapy research lacks a humanized solid tumor model simulating clinical practice, and there is no reliable platform to evaluate the safety and effectiveness of tumor immunotherapy, which is also one of the main bottlenecks in the field of tumor immunotherapy research.on June 23, 2020, Professor Xu Yang and Professor Fu Xuemei from the eighth Affiliated Hospital of Sun Yat sen University, Professor Wang Lei from the University of California, San Francisco, and researcher Wang Qian from Hangzhou Institute of physical and Chemical Technology, Chinese Academy of Sciences, jointly published the title "developing valuable protein drugs via proximity enabled reactive" in cell magazine The research papers of therapeutics lay a foundation for further research and development of covalent protein drugs.in 2018, Professor Wang Lei inserted a non-toxic unnatural amino acid, fluorosulfur-l-tryptophan (fsy), into the model protein by using the extended genetic code technology. The protein modified by fsy can bind to the lysine, histidine and tyrosine residues of the corresponding sites on the protein ligand A click chemical reaction sulfur fluorine exchange reaction occurs, which results in CO bond crosslinking [5].the research results lay a foundation for further research and development of covalent protein drugs.in this study, when fsy was inserted into a specific site in the extracellular domain of PD-1 protein, fsy modified PD-1 (pd-1fsy) could covalently crosslink with PD-L1, irreversibly blocking the binding of PD-L1 on tumor cell surface and PD-1 on T cell surface (Fig. 1).in order to further verify the application prospect of this technology platform in the development of covalent protein drugs, the researchers inserted fsy into the specific position of antibody targeting HER2, and the modified antibody can covalently cross-linked with HER2.Fig. 1. Overview of paper ideas: in order to study the function of pd-1fsy in the treatment of solid tumors, the research team needs to solve the bottleneck problem of lack of humanized solid tumor animal models that simulate clinical practice.the team of Professor Xu Yang and Professor Fu Xuemei have made a series of important achievements in the development and application of humanized mice of immune system [6,7], and in this research, we have created a solid tumor model of immune system humanized mice, which has a clinical closely related immunosuppressive microenvironment.using this new model, the research team has proved that pd1fsy protein drugs are more effective in eliminating solid tumors with immunosuppressive microenvironment than traditional antibody drugs, highlighting the clinical application prospect of covalent protein drugs in tumor immunotherapy. this study further demonstrated the advantages of the humanized solid tumor model of the immune system in the evaluation of the efficacy and safety of tumor immunotherapy drugs. the research results of this paper lay the foundation for the research and development of covalent protein drugs, and showed the great application prospects of covalent protein drugs in the field of tumor immunotherapy. in addition, in addition to developing therapeutic protein drugs, covalent protein technology will become a widely used synthetic biological platform in the fields of disease diagnosis, single cell analysis, and new antibody research and development. Li Qingke and Chen Qu, doctoral students of Southern Medical University, and Paul C. Klauser of the University of California, San Francisco, are co authors of the paper. Professor Wang Lei, Professor Xu Yang and researcher Wang Qian are the co authors of this paper. original link: plate maker: old wings, references 1. Johnson, D.S., weerapana, e., and cravat, B.F. (2010). Strategies for discovery and derisking valuable, irreversible enzymeinhibitors. Future Med.Chem . 2, 949–964.2.Lonsdale,R.,and Ward,R.A. (2018). Structure-baseddesign oftargeted covalent inhibitors.Chem . Soc. Rev. 47, 3816–3830.3.Singh,J.,Petter,R.C.,Baillie,T.A.,andWhitty,A.(2011).Theresurgenceofcovalentdrugs. Nat. Rev. Drug Discov. 10, 307–317.4.  Lee,C.M., and Tannock, I.F. (2010). The distribution of the therapeutic monoclonalantibodies cetuximab and trastuzumab within solid tumors. BMC Cancer 10, 255.5.Wang,N., Yang, B., Fu, C., Zhu, H., Zheng, F., Kobayashi, T., Liu, J., Li, S., Ma, C.,Wang, P.G., et al. 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