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Large-Scale CRISPR Screen of LDLR Pathogenic Variants

Research 2024年第2期2023卷 213-225页

作者： Mengjing Li Lerong Ma Yiwu Chen Jianing Li Yanbing Wang Wenni You Hongming Yuan Xiaochun Tang Hongsheng Ouyang Daxin Pang key lab for Zoonoses Research Ministry of EducationAnimal Genome Editing Technology Innovation CenterCollege of Animal SciencesJilin UniversityChangchunJilin Province 130062China The Institute of Translational Medicine Tianjin Union Medical Center of Nankai UniversityTianjin 300071China Chongqing ResearchInstitute Jilin UniversityChongqing 401123China Chongqing Jitang biotechnology Research Institute Co.Ltd. ChongqingChina

Familial hypercholesterolemia(FH)is a frequently occurring genetic disorder that is linked to early-onset cardiovascular *** left untreated,patients with this condition can develop severe cardiovascular ***,many patients remain undiagnosed,and even when diagnosed,the treatment is often not *** mutations in the LDLR gene are the primary cause of FH,predicting whether novel variants are pathogenic is not a straightforward *** the functionality of LDLR variants is crucial in uncovering the genetic basis of *** study utilized CRISPR/Cas9 cytosine base editors in pooled screens to establish a novel approach for functionally assessing tens of thousands of LDLR variants on a large scale.A total of more than 100 single guide RNAs(sgRNAs)targeting LDLR pathogenic mutations were successfully screened with relatively high *** of these,5 sgRNAs were further subjected to functional verification studies,including 1 in the promoter,1 in the antisense RNA,1 in the exon,and 2 in the *** for the variant caused by the sgRNA located at intron 16,the functionalities of the other LDLR variants were all *** high similarity of LDLR intron sequences may lead to some false ***,these results confirm the reliability of the large-scale screening strategy for functional analysis of LDLR variants,and the screened candidate pathogenic mutations could be used as an auxiliary means of clinical gene detection to prevent FH-induced heart disease.

关键词： LDLR Screen straight

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Practical Synthesis of Valbenazine via 1,3-Dipolar Cycloaddition

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Chinese Journal of Chemistry 2024年第8期42卷 841-845页

作者： Yalan Peng Zuming Lin Lili Zhu Shiqing Han Sha-Hua Huang Ran Hong College of biotechnology and pharmaceutical Engineering Nanjing Tech UniversityNanjingJiangsu211816 China School of Environmental and Chemical Engineering Shanghai Institute of TechnologyShanghai201418 China State key laboratory of Chemical Biology Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai200032 China Innovation Research Institute of Traditional Chinese Medicine(IRI) Shanghai University of Traditional Chinese Medicine1200 Cailun RoadShanghai201203 China

Comprehensive Summary,Valbenazine(Ingrezza),a potent and highly selective inhibitor of vesicular monoamine transporter type 2(VMAT2)through the active metabolite hydrotetrabenazine(HTBZ),has been approved for the treatment of tardive dyskinesia and,very recently,for chorea,which is associated with Huntington's *** numerous synthetic efforts dedicated to the synthesis of HTBZ,the industrial preparation of valbenazine uses dihydroisoquinoline as a starting material and the chiral resolution of racemic HTBZ derived from ketone ***,we present a practical synthesis of HTBZ and valbenazine featuring a highly stereoselective 1,3-dipolar cycloaddition and enzymatic kinetic *** cascade process includes cycloaddition,N—O bond cleavage,and lactamization,which proved to be operationally *** allure of the enzymatic resolution developed in this work offers a rapid access toward affording tetrahydroisoquinoline(THIQ)-fused piperidine in the production of medically significant compounds,such as yohimbine and reserpine.

关键词： Cycloaddition Chemoenzymatic Kinetic resolution Prodrugs VMAT2 inhibitor

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A new autophagy-related nomogram and mechanism in multiple myeloma

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Genes & Diseases 2024年第5期11卷 29-32页

作者： Hanying Huang Yang Li Ziang Zhu Yang Liu Weida Wang Shuzhao Chen Xiaoping Wu Yun Wang Yanzhou Chen Huanxin Lin Yang Liang Lingling Shu State key laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhouGuangdong 510060China Department of Hematologic Oncology Sun Yat-sen University Cancer CenterGuangzhouGuangdong 510060China Department of Radiation Oncology Sun Yat-sen University Cancer CenterGuangzhouGuangdong 510060China key laboratory of Neurosurgery in Guangdong Province Southern Medical UniversityGuangzhouGuangdong 510060China Department of Neurosurgery Zhujiang HospitalSouthern Medical UniversityGuangzhouGuangdong 510060China State key laboratory of pharmaceutical biotechnology The University of Hong KongHong Kong 999077China

Multiple myeloma(MM)is the second most common hematological *** is characterized by high drug resistance,easy recurrence,and poor prognosis,and remains *** models or scoring modalities can be used to predict the survival prognosis of MM patients;however,these predictions are still not accurate *** have previously found that scorings related to bone marrow microenvironment metabolism can improve predictive efficacy.

关键词： metabolism prognosis myeloma

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Photomediated core modification of diaryl dihydrophenzines through three-component alkylarylation of alkenes toward organocatalyzed ATRP

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Green Synthesis and Catalysis 2024年第1期5卷 35-41页

作者： Yajun Zhang Hao Wang Dandan Jiang Naixian Sun Wei He Lili Zhao Ning Qin Ning Zhu Zheng Fang Kai Guo College of biotechnology and pharmaceutical Engineering State Key Laboratory of Materials-Oriented Chemical EngineeringNanjing Tech UniversityNanjing211800China Institute of Advanced Synthesis School of Chemistry and Molecular EngineeringNanjing Tech UniversityNanjing211800China Department of Mechanical Engineering The University of SheffieldSheffieldS13JDUnited Kingdom

The design and synthesis of a novel organic photocatalyst(OPC)have attracted broad interest from both the organic chemistry and polymer ***,we presented a visible-light-induced alkylarylation of alkenes strategy for core modification of 5,10-diaryl-5,10-dihydrophenazines(DADHPs)under metal-and additive-free conditions,with the aim to develop powerful photocatalyst for organocatalyzed atom transfer radical polymerization(O-ATRP).Good tolerance for a wide variety of functional groups and affording the corresponding tetrasubstituted products in moderate to good yields were achieved in the batch and flow *** experimental and computational mechanistic study confirmed that DADHPs’radical cations andπ-πstacking interactions played important roles in the alkylarylation of alkenes.A series of the tetrasubstituted DADHPs were directly synthesized from the corresponding noncore-modified phenazines,which were demonstrated to be effective organic photoredox catalysts for *** responsive nature,controlled polymerization manner,and welldefined poly(methyl methacrylate)were achieved via tetrasubstituted DADHPs mediated O-ATRP.

关键词： Photoinduced Core modification Diaryl dihydrophenzine O-ATRP

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解密baccatin Ⅲ生物合成途径,奠定紫衫烷可持续获取途径

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Science Bulletin 2024年第9期69卷 1182-1184页

作者：谭仁祥陈晓亚 State key laboratory of pharmaceutical biotechnology Institute of Functional BiomoleculesSchool of Life SciencesNanjing UniversityNanjing 210023China State key laboratory of Plant Molecular Genetics CAS Center for Excellence in Molecular Plant SciencesChinese Academy of SciencesShanghai 200032China

The characterization and reconstitution of Taxus enzymes leading to taxoids (diterpenoids with the taxane skeleton seen in the taxol molecule)[1–5] are exciting and may tempt researchers to update the episode about t... 详细信息

关键词： prescribed skeleton baccatin

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Advances in the study of protein folding and endoplasmic reticulum-associated degradation in mammal cells

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Journal of Zhejiang University-Science B(Biomedicine & biotechnology) 2024年第3期25卷 212-232页

作者： Hong CAO Xuchang ZHOU Bowen XU Han HU Jianming GUO Yuwei MA Miao WANG Nan LI Jun ZOU Department of Sport Rehabilitation Shanghai University of SportShanghai 200438China national key laboratory of Immunity and Inflammation Naval Medical UniversityShanghai 200433China

The endoplasmic reticulum is a key site for protein production and quality *** than one-third of proteins are synthesized and folded into the correct three-dimensional conformation in the endoplasmic ***,during protein folding,unfolded and/or misfolded proteins are prone to occur,which may lead to endoplasmic reticulum *** can monitor the quality of the proteins produced by endoplasmic reticulum quality control(ERQC)and endoplasmic reticulum-associated degradation(ERAD),which maintain endoplasmic reticulum protein homeostasis by degrading abnormally folded *** underlying mechanisms of protein folding and ERAD in mammals have not yet been fully ***,this paper reviews the process and function of protein folding and ERAD in mammalian cells,in order to help clinicians better understand the mechanism of ERAD and to provide a scientific reference for the treatment of diseases caused by abnormal ERAD.

关键词： Endoplasmic reticulum-associated degradation(ERAD) Protein folding Ubiquitination Retrotranslocation

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Targeting STING oligomerization with licochalcone D ameliorates STING-driven inflammatory diseases

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Science China Life Sciences 2024年

作者： Yinghui Zhang Yadan Liu Bing Jiang Lifan Chen Jie Hu Buying Niu Jie Chang Zisheng Fan Jingyi Zhou Yajie Wang Dan Teng Ning Ma Xiaofeng Wang Ruirui Yang Mingyue Zheng Sulin Zhang Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences University of Chinese Academy of Sciences School of Chinese Materia Medica Nanjing University of Chinese Medicine Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology Shanghai Tech University School of Physical Science and Technology ShanghaiTech University School of pharmaceutical Science and Technology Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences State key laboratory of pharmaceutical biotechnology Nanjing University

The development of STING inhibitors for the treatment of STING-related inflammatory diseases continues to encounter significant challenges. The activation of STING is a multi-step process that includes binding with cGAMP, self-oligomerization, and translocation from the endoplasmic reticulum to the Golgi apparatus, ultimately inducing the expression of IRF3 and NF-κB-mediated interferons and inflammatory cytokines. It has been demonstrated that disruption of any of these steps can effectively inhibit STING activation. Traditional structure-based drug screening methodologies generally focus on specific binding sites. In this study, a TransformerCPI model based on protein primary sequences and independent of binding sites is employed to identify compounds capable of binding to the STING protein. The natural product Licochalcone D（LicoD） is identified as a potent and selective STING inhibitor. LicoD does not bind to the classical ligandbinding pocket; instead, it covalently modifies the Cys148 residue of STING. This modification inhibits STING oligomerization, consequently suppressing the recruitment of TBK1 and the nuclear translocation of IRF3 and NF-κB. LicoD treatment ameliorates the inflammatory phenotype in Trex1-/-mice and inhibits the progression of DSS-induced colitis and AOM/DSS-induced colitis-associated colon cancer（CAC）.In summary, this study reveals the potential of LicoD in treating STING-driven inflammatory diseases. It also demonstrates the utility of the TransformerCPI model in discovering allosteric compounds beyond the conventional binding pockets.

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An Update on the Clinical Pipelines of New Antibacterial Drugs Developed in China

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Engineering 2024年第7期38卷 52-68页

作者： Xinyi Yang Congran Li Xiukun Wang Zhonghui Zheng Peiyi Sun Chunjie Xu Luni Chen Jiandong Jiang Staffan Normark Birgitta Henriques-Normark Xuefu You Beijing key laboratory of Antimicrobial Agents/laboratory of Pharmacology Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Division for Medicinal Microorganism-Related Strains CAMS Collection Center of Pathogenic MicroorganismsChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China State key laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Shandong Xinhua pharmaceutical Co. Ltd.Zibo 255005China Department of Microbiology Tumor and Cell BiologyKarolinska InstitutetStockholm SE-17177Sweden State key laboratory of Bioactive Substances and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Institute of Medicinal biotechnology Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Clinical Microbiology Karolinska University HospitalBioclinicumStockholm SE-17176Sweden

Antibacterial resistance is a global health threat that requires further concrete action on the part of all *** this context,one of the biggest concerns is whether enough new antibacterial drugs are being discovered and *** several high-quality reviews on clinical antibacterial drug pipelines from a global perspective were published recently,none provides comprehensive information on original antibacterial drugs at clinical stages in *** this review,we summarize the latest progress of novel antibacterial drugs approved for marketing and under clinical evaluation in China since *** was obtained by consulting official websites,searching commercial databases,retrieving literature,asking personnel from institutions or companies,and other means,and a considerable part of the data covered here has not been included in other *** of June 30,2023,a total of 20 antibacterial projects from 17 Chinese pharmaceutical companies or developers were identified and *** them,two new antibacterial drugs that belong to traditional antibiotic classes were approved by the national Medical Products Administration(NMPA)in China in 2019 and 2021,respectively,and 18 antibacterial agents are in clinical development,with one under regulatory evaluation,five in phase-3,six in phase-2,and six in *** of the clinical candidates are new analogs or monocomponents of traditional antibacterial pharmacophore types,including two dual-acting hybrid antibiotics and a recombinant antibacterial ***,despite there being 17 antibacterial clinical candidates,our analysis indicates that there are still relatively few clinically differentiated antibacterial agents in stages of clinical development in ***,Chinese pharmaceutical companies and institutions will develop more innovative and clinically differentiated candidates with good market potential in the future research and development(R&D)of original antibacterial drugs.

关键词： Antimicrobial resistance New antibiotics Clinical pipelines WHO priority pathogens national Mega-Project for Innovative Drugs

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TBC1D1 is an energy-responsive polarization regulator of macrophages via governing ROS production in obesity

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Science China Life Sciences 2024年第9期67卷 1899-1914页

作者： Qi Wang Ping Rong Wen Zhang Xinyu Yang Liang Chen Ye Cao Minjun Liu Weikuan Feng Qian Ouyang Qiaoli Chen Hailong Li Hui Liang Fanguo Meng Hong-Yu Wang Shuai Chen State key laboratory of pharmaceutical biotechnology Department of Cardiology Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School Model Animal Research CenterSchool of Medicine Nanjing University MOE key laboratory of Model Animal for Disease Study Department of Endocrinology Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School Model Animal Research Center School of Medicine Nanjing University College of Life Science Anhui Medical University Redox Medical Center for Public Health Medical College of Soochow University Department of General Surgery First Affiliated Hospital Nanjing Medical University

Energy status is linked to the production of reactive oxygen species（ROS） in macrophages, which is elevated in obesity. However, it is unclear how ROS production is upregulated in macrophages in response to energy overload for mediating the development of obesity. Here,we show that the Rab-GTPase activating protein（Rab GAP） TBC1D1, a substrate of the energy sensor AMP-activated protein kinase（AMPK）,is a critical regulator of macrophage ROS production and consequent adipose inflammation for obesity development. TBC1D1 deletion decreases, whereas an energy overload-mimetic non-phosphorylatable TBC1D1S231AAmutation increases, ROS production and M1-like polarization in macrophages. Mechanistically, TBC1D1 and its downstream target Rab8a form an energy-responsive complex with NOX2 for ROS generation. Transplantation of TBC1D1S231Abone marrow aggravates diet-induced obesity whereas treatment with an ultra-stable Tt SOD for removal of ROS selectively in macrophages alleviates both TBC1D1S231Amutation-and diet-induced obesity. Our findings therefore have implications for drug discovery to combat obesity.

关键词： TBC1D1 AMPK Rab8a NOX2 ROS inflammation macrophage obesity

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Gene-knockout by iSTOP enables rapid reproductive disease modeling and phenotyping in germ cells of the founder generation

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Science China(Life Sciences) 2024年第5期67卷 1035-1050页

作者： Yaling Wang Jingwen Chen Xueying Huang Bangguo Wu Peng Dai Feng Zhang Jinsong Li Lingbo Wang State key laboratory of Genetic Engineering Shanghai Key Laboratory of Metabolic Remodeling and HealthInstitute of Metabolism and Integrative BiologyFudan UniversityShanghai 200438China Institute of Reproduction and Development Obstetrics and Gynecology HospitalFudan UniversityShanghai 200011China NHC key lab of Reproduction Regulation(Shanghai Institute for Biomedical and pharmaceutical Technologies) School of PharmacyFudan UniversityShanghai 200433China Shanghai key laboratoryof Maternal and Fetal Medicine Clinical and Translational Research Center of Shanghai First Maternity and Infant HospitalFrontier Science Center for Stem Cell ResearchSchoolof Life Sciences and TechnologyTongji UniversityShanghai 200092China State key laboratory of Cell Biology CAS Center for Excellence in Molecular Cell ScienceShanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghai 200031China

Cytosine base editing achieves C·G-to-T·A substitutions and can convert four codons(CAA/CAG/CGA/TGG)into STOP-codons(induction of STOP-codons,iSTOP)to knock out genes with reduced *** enables direct phenotyping in founders’somatic cells,but it remains unknown whether this works in founders’germ cells so as to rapidly reveal novel genes for ***,we initially establish that iSTOP in mouse zygotes enables functional characterization of known genes in founders’germ cells:Cfap43-iSTOP male founders manifest expected sperm features resembling human“multiple morphological abnormalities of the flagella”syndrome(i.e.,MMAF-like features),while oocytes of Zp3-iSTOP female founders have no zona *** further illustrate iSTOP’s utility for dissecting the functions of unknown genes with Ccdc183,observing MMAF-like features and male infertility in Ccdc183-iSTOP founders,phenotypes concordant with those of Ccdc183-KO *** ultimately establish that CCDC183 is essential for sperm morphogenesis through regulating the assembly of outer dynein arms and participating in the intra-flagellar *** study demonstrates iSTOP as an efficient tool for direct reproductive disease modeling and phenotyping in germ cells of the founder generation,and rapidly reveals the essentiality of Ccdc183 in fertility,thus providing a time-saving approach for validating genetic defects(like nonsense mutations)for human infertility.

关键词： disease modeling infertility multiple morphological abnormalities of the flagella(MMAF) induction of STOP-codons(iSTOP CRISPR-STOP) sperm motility

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