Table of Content

22 October 2021, Volume 43 Issue 5

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Special Issue for Advanced Immunochemical Studies

Function and mechanism of PIWI/piRNA in cancer

SHI Shuo, WANG Chen, LIN Haifan

2021, 43(5):  313-322.  doi:10.3969/j.issn.0253-9608.2021.05.001

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PIWI proteins, a subfamily of PAZ/PIWI domain (PPD) family RNA-binding proteins, are best known for their functions in silencing transposons and germline development by partnering with small noncoding RNA called PIWI-interacting RNA (piRNA). In addition to its prominent role in the germline, PIWI proteins are gaining increasing interests for cancer research because they are usually hardly expressed in somatic tissues but gain abnormal expression in cancer cells, making them promising targets for precision therapy. In this review, we first provide an overview on how PIWI proteins, together with piRNAs, multifacetedly regulate the expression of major classes of RNA in germ cells. Then, we summarize the expression and function of PIWI proteins and piRNAs in different types of cancer and consider the limitations and possible misunderstanding of PIWI and piRNA in cancer research. In addition, we discuss the recently discovered piRNA-independent functions and regulatory mechanisms of PIWI in cancer cells that have the traditional concept.



Disulfide re-bridging for the construction of homogeneous antibody-drug conjugates

HUANG Rong, CHEN Hongli, JIANG Biao

2021, 43(5):  323-334.  doi:10.3969/j.issn.0253-9608.2021.05.002

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Antibody-drug conjugates (ADCs) combine an antibody with highly potent drugs by chemical linkers, allowing to have both the efficacy of payloads and the targeting ability of antibodies for targeted and precise therapeutics. Currently, 10 ADCs have been approved by FDA. It is very important to develop site-specific conjugation method to obtain homogeneous ADCs with controllable drug-antibody ratio (DAR) for the next generation of ADCs. Recently, the “ThioBridge” method that is based on the reduction and re-bridging of the disulfides in an antibody has demonstrated its advantages: a direct chemical method to site-specific modify native antibody, wide applicability, controllable DAR and high homogeneity. Here, we briefly introduce the recent development and progress of disulfide re-bridging methods to construct homogeneous ADCs.



Progress on structures of anti-tuberculosis drug targets

CHEN Xiaobo , LI Jun

2021, 43(5):  335-342.  doi:10.3969/j.issn.0253-9608.2021.05.003

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Tuberculosis, mainly caused by the pathogenic bacteria Mycobacterium tuberculosis , is an infectious disease that seriously threats human life and health. The even worse situation currently is the drug resistance problem. Thus, new anti-tuberculosis drugs are urgently needed. Studies on the structures of anti-tuberculosis drug targets will assist in drug development. This paper summarizes
the latest research progress on structures of the crucial drug targets involved in the two important physiology processes of cell wall biosynthesis and energy metabolism in Mycobacterium tuberculosis , and also analyzes the structure-function relation of these
membrane proteins and their complexes as well as the precise mode of actions of the known drug molecules on these targets, and the important value for the design of new anti-tuberculosis drugs.




Study of structural biology and inhibition mechanisms of important drug targets of SARS-CoV-2

GAO Hailong , WANG Haofeng , ZHAO Yao , GAO Yan , WANG Quan

2021, 43(5):  343-348.  doi:10.3969/j.issn.0253-9608.2021.05.004

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So far, more than 200 million people were infected and millions of people have died during this worldwide COVID-19 pandemic. In response to the SARS-CoV-2, the pathogen of the epidemic, scientists have carried out in-depth and detailed researches on its drug targets. The analysis of the three-dimensional structures of drug target proteins has guiding significance for people to understand the mechanism of drug candidates and develop new drugs. This article summarizes the structures of the main protease and transcription-replication complex of SARS-CoV-2, analyzes the mechanism of small molecules inhibiting the corresponding target protein, and elucidates the significance in fighting the COVID-19 pandemic.




Structure and transcriptional regulation mechanism of Mediator complex

ZHANG Heqiao, NIE Yan

2021, 43(5):  349-358.  doi:10.3969/j.issn.0253-9608.2021.05.005

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n eukaryotes, the Mediator complex receives transcriptional activation signals carried by transcriptional activators/gene-specific transcription factors and transmits them to the core transcriptional machinery, RNA polymerase II, acting as a bridge in this process. The Mediator complex interacts with RNA polymerase II and various general transcription factors to form the pre-initiation
complex, which is required for the transcription of almost all genes in eukaryotes. The subunit composition of the Mediator complex is complex and varied, and its conformation is flexible. The structural biology and transcriptional regulation mechanism of the Mediator complex have been studied for more than 30 years. In this review, the discovery, function, subunit composition and structural biology of the Mediator complex are summarized, and their possible transcriptional regulatory mechanisms are briefly discussed.




Development and application of C₂H₂ zinc finger protein-based drug delivery technology

LI Lu, WEI Xuan, LIU Jia

2021, 43(5):  359-364.  doi:10.3969/j.issn.0253-9608.2021.05.006

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Zinc finger proteins (ZFPs) are widespread transcription factors in eukaryotes and play important roles in gene expression
regulation. Recent studies have shown that C₂H₂ ZFPs can penetrate mammalian cells through macropinocytosis. In further studies, we have found that C₂H₂ ZFPs are capable of achieving highly efficient cellular delivery of a wide range of proteins including both reporter proteins and therapeutic proteins, with superior cell-penetrating activity to traditional cell-penetrating peptides (CPPs). In this review, we introduce the basic biology and the cell-penetrating activities of ZFPs, and discuss the application of C₂H₂ ZFPs in macromolecular drug delivery.




Recent progress in development of immunodeficient rat models

SONG Song, ZHU Xianmin, FAN Guoping

2021, 43(5):  365-373.  doi:10.3969/j.issn.0253-9608.2021.05.007

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Immunodeficient animal models are generated for biomedical research by spontaneous mutations or genome editing to remove one or more components of the immune system. Immunodeficient mice models have been well established, which provide good tools for many research areas such as humanize mice, patient-derived xenograft (PDX), stem cell transplantation and infectious diseases. Compared with mice, however, rats have the advantages of large size, more similar to human metabolically and  physiologically, easier surgical operation and sample collection, and long-term applicated in preclinical toxicology and pharmacology. Therefore, in recent years, a variety of immunodeficient rat models have emerged. By comparing different animal models, this review mainly focuses on the recent advances in immunodeficient rat models, and discusses their potential applications in stem cell and antitumor therapy.



Advances in combinatorial antibody library

QIANG Min, SHI Xiaojie, ZHANG Chuyue, MA Peixiang, YANG Guang

2021, 43(5):  374-382.  doi:10.3969/j.issn.0253-9608.2021.05.008

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Combinatorial antibody library is a key strategy in immunochemistry, which aims to establish libraries of large capacity and high diversity in vitro. It integrates the genotype and phenotype in the screening system to allow the molecule to self-replicate. It leverages the principle of biological evolution to perform high-throughput screening. This technology allows the reconstruction of an immune system in a test tube and empowers the antibody selection without the constraints of animals or organs. It records the donors’ immune response by molecular clone. The random recombination of heavy and light chains can avoid immunologic tolerance and discover rare antibodies. Due to the development of immunochemistry, the combinatorial antibody library technology keeps updating. Novel screening approaches have emerged, such as autocrine cell-based selection system and cell-cell interaction based system. Here, we introduce the development of combinatorial antibody library technology.



Computational drug design methods by deep learning algorithms 

LI Fenglei, HU Qiaoyu, XIONG Ruofan, BAI Fang

2021, 43(5):  383-390.  doi:10.3969/j.issn.0253-9608.2021.05.009

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Drug design and development is a long term, expensive and high-risk process. The continuous innovation of science and technology, as well as the explosive growth of the biomedical data brings unprecedented opportunities for the applications of deep learning algorithms in biomedical areas to expediate the drug development. In this review, we briefly overview and list the state-ofthe-art deep learning-driven drug design methods for identifying drug targets, molecular generation, ligand-based and structure-based drug design.