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Novel PF74-like small molecules targeting the HIV-1 capsid protein:Balance of potency and metabolic stability

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Acta Pharmaceutica Sinica B 2021年第3期11卷 810-822页

作者： Lei Wang Mary CCasey Sanjeev Kumar VVernekar Rajkumar Lalji Sahani Karen AKirby Haijuan Du Huanchun Zhang Philip RTedbury Jiashu Xie Stefan GSarafianos Zhengqiang Wang Center for Drug Design College of PharmacyUniversity of MinnesotaMN 55455USA Department of Pharmaceutical Sciences School of Chemical EngineeringDalian University of TechnologyDalian 116024China Department of Molecular Microbiology and Immunology University of Missouri School of MedicineChristopher S.Bond Life Sciences CenterColumbiaMO 65211USA Laboratory of Biochemical Pharmacology Department of PediatricsEmory University School of MedicineAtlantaGA 30322USA

Of all known small molecules targeting human immunodeficiency virus(HIV)capsid protein(CA),PF74 represents by far the best characterized chemotype,due to its ability to confer antiviral phenotypes in both early and late phases of viral ***,the prohibitively low metabolic stability renders PF74 a poor antiviral *** report herein our medicinal chemistry efforts toward identifying novel and metabolically stable small molecules targeting the PF74 binding ***,we replaced the inter-domain-interacting,electron-rich indole ring of PF74 with less electron-rich isosteres,including imidazolidine-2,4-dione,pyrimidine-2,4-dione,and benzamide,and identified four potent antiviral compounds(10,19,20 and 26)with markedly improved metabolic *** to PF74,analog 20 exhibited similar submicromolar potency,and much longer(51-fold)half-life in human liver microsomes(HLMs).Molecular docking corroborated that 20 binds to the PF74 binding site,and revealed distinct binding interactions conferred by the benzamide ***,our data support compound 20 as a promising antiviral lead.

关键词： HIV-1 capsid protein PF74 Microsomal stability

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Expression and Characterization of a Recombinant Truncated capsid protein of Hepatitis E Virus in Pichia pastoris

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Chemical Research in Chinese Universities 2010年第2期26卷 235-239页

作者： YANG En-cheng CHI Bao-rong LI Xiao LIU Yan GAO Peng JIA Peng KAN Shi-fu WEN Zhong-mei WANG Wan JIN Ning-yi The First Hospital of Jilin University Changchun 130021 P R. China Genetic Engineering Laboratory of PLA Academy of Military Medical Sciences Changchun 130062 P. R. China The Hospital of Digestive Diseases People＇s Hospital of Heilongjiang Province Harbin 150001 P. R. China Department of Pharmacy the First Hospital of Harbin Medical University Harbin 150001 P. R. China

Hepatitis E is an enterically transmitted viral disease caused by infection with hepatitis E virus（HEV）. HEV is a nonenveloped virus that bas been classified in the family of Caliciviridae. The virus appears to be a polya-denylated, positive-stranded RNA virus with three major open reading frames（ORFs）. The capsid protein of HEV is encoded by the open reading frame 2（ORF2）. We attempted to produce a truncated capsid protein, designed p293, in Pichia pastoris. The p293 gene encoding amino acids（aa） 382-674 of HEV ORF2 was designed based on the full length of HEV ORF2, cloned into the yeast vector pPIC9K, and expressed in P. pastoris strain GS 115. SDS-PAGE and Western blotting demonstrated that the recombinant protein p293 could well be expressed in P pastoris. Under optimized conditions （culture medium pH, 6.0-6.5; methanol concentration added daily, 3.0%; inoculum density, OD600=60; induction time point, 72-96 h）, the yield of soluble p293 was approximately 80 mg/L. We also observed p293 secretory expressed in P. pastoris to be 30 nm viral like particles by using electron microscopy. These results show that the p293 may has utility in the analysis of cell specific factors in the protein processing and assembly of HEV, and serve as a useful antigen for both diagnostic and vaccine purposes.

关键词： Hepatitis E virus capsid protein Pichiapastoris protein purification

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Development of an indirect immunofluorescence assay for PCV3 antibody detection based on capsid protein

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Animal Diseases 2021年第2期1卷 125-132页

作者： Lun Yao Chang Li Junwei Wang Yufang Cheng Ahmed H.Ghonaim Qi Sun Xuexiang Yu Weijie Niu Shengxian Fan Qigai He State Key Laboratory of Agricultural Microbiology Huazhong Agricultural UniversityWuhanChina The Cooperative Innovation Center for Sustainable Pig Production Huazhong Agricultural UniversityWuhanChina College of Veterinary Medicine Huazhong Agricultural UniversityWuhanChina

Porcine circovirus type 3(PCV3)is a novel porcine circovirus associated with porcine dermatitis and nephritis syndrome(PDNS),reproductive failure,and multisystemic *** protein(Cap)encoded by PCV3 ORF2 gene has been identified as an immunogenic ***,there is no immunofluorescence assay(IFA)available for serological ***,the N-terminal 33 amino acids of Cap protein were predicted to serve as a PCV3 nuclear localization signal(NLS).Two types of recombinant plasmids were constructed for recombinant protein expression in 5f9 cells by using a baculovirus expression system:plasmid rvBac-Pc for full-length Cap protein expression and rvBac-Sc for Cap protein expression with a honeybee melittin signal peptide in place of the predicted NLS *** of the nuclear localization sequences was further analyzed by *** and specific fluorescence signals were observed in the nucleus of rvBac-Pc-transfected cells and in the cytoplasm of rvBac-Sc-transfected *** cross-reactivity was observed with porcine circovirus type 2,porcine pseudorabies virus,classical swine fever virus,or porcine reproductive and respiratory syndrome *** summary,we developed two fluorescence detection modes for Cap protein that can be used to detect PCV3 *** method is suitable for the diagnosis and epidemiological investigation of *** study provides a reliable detection method for monitoring PCV3 antibody level in pigs in the future.

关键词： PCV3 capsid protein Antibodies IFA

Evidence for lentivirus capsid protein interaction with dynein motors:Insights to drug design targeting viral retrograde transport

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Evidence for lentivirus capsid protein interaction with dyne...

Generation and Characterization of Monoclonal Antibodies Against Red-Spotted Grouper Nervous Necrosis Virus(RGNNV)

第十一届中国细胞生物学学术大会暨2009西安细胞生物学...

作者： Yang Su Wentao Qiao Yunqi Geng Jun zhou Qimin Chen Key Laboratory of Molecular Microbiology and Biotechnology(Ministry of Education) and Key Laboratory of Microbial Functional Genomics(Tianjin) College of Life Sciences Nankai University Tianjin 300071 China

＜正＞Intracellular virus particles embezzle the host transport system to translocate the cytoplasm. Cytoplasmic dynein as well as the dynactin complex are microtubule-associated motors and responsible for virus motion through cell periphery to perinuclear viral replication site. Lentiviruses,such as noted human immunodeficiency virus（HIV）,travel along the microtubule

关键词： dynein capsid protein bovine immunodeficiency virus

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Journal of Ocean University of China 2022年第4期21卷 1061-1067页

作者： QIN Yinghui LIU Jiaoyun LU Yuanan LIU Xueqin College of Fisheries Huazhong Agricultural UniversityWuhan 430070China Hubei Engineering Technology Research Center for Aquatic Animal Diseases Control and Prevention Wuhan 430070China Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt Ministry of EducationWuhan 430070China Department of Public Health Sciences University of Hawaii at ManoaHonoluluHI 96822USA

Nervous necrosis virus(NNV)can infect more than 120 fish species worldwide and has caused high mortality and sig-nificant economic losses to the aquaculture *** different genotypes of NNV,the red-grouper nervous necrosis virus(RGNNV)is the most widely distributed one with the highest number of susceptible fish *** this study,the capsid protein(Cp)gene of RGNNV was recombined and expressed in Escherichia coli strain BL21(DE3)and the recombinant Cp(rCp)was used as an immunogen to produce monoclonal antibodies(MAbs)through hybridoma cell fusion *** MAbs were produced and characterized by indirect enzyme-linked immunosorbent assay(ELISA),western blotting,and immunofluorescence assay(IFA).Wes-tern blotting result showed that the MAbs could specifically react with the capsid protein of *** result of IFA showed that the MAbs could recognize virions in RGNNV-infected grouper spleen(GS)*** results indicate that the MAbs can specifi-cally recognize RGNNV virions and can be used to produce a rapid detection *** study provides a foundation for further studies on the rapid diagnosis of RGNNV and its infection mechanisms.

关键词： RGNNV monoclonal antibody capsid protein grouper

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Effects of Site-directed Mutagenesis of L469 in Helix-5 of Human Papillomavirus 16 L1 on Pentamer Formation

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Chemical Research in Chinese Universities 2017年第3期33卷 392-399页

作者： PAN Dong WANG Lincong LIU Meiyi JIN Shi WANG Liyan YU Xianghui ZHA Xiao WU Yuqing State Key Laboratory of Supramoleeular Structure and Materials College of Computer Science and Technology Institute of Theoretical Chemistry State Engineering Laboratory of AIDS Vaccine Jilin University Changehun 130012 P. R. China Sichuan Cancer Hospital & Institute Chengdu 610041 P. R. China

Located at the carboxyl terminal of the human papillomavirus major capsid protein L1, helix-5（h5） is cru-cial to L1 folding and pentamer formation. Site-directed mutagenesis of the leucine residue on site 469 into lysine, alanine, serine and glycine was performed to explore the effect of the resultant mutations on L 1 pentamer formation. The soluble yields of the L1 pentamers of the L469A and L469K mutants were nearly two fold higher than that of the wild type. Molecular dynamics simulation was then performed to reveal the intrinsic mechanisms involved in the improvement of L 1 pentamer yield. Accordingly, the secondary structures of h5, β-G2, β-B1, β-C, β-D, and β-F were altered. The altered structures improved the hydrophobic interaction between h5 and fl-core ＂jelly＂ and the stability of h5. The hydrophobic surface area of residue 469 was reduced by 50% relative to that of the wild type. The C--O group of residue 469 and C--N group of L470 were both exposed to the solvent in the L469A mutant. These modifications may account for the increased solubility and stability and the promotion of pentamer formation induced by the point mutation. Therefore, the changes in the hydrophobic properties of h5 and the core structure determined the pentamer formation and solubility. This study may assist the development of a cost-effective platform for the production of prophylactic virus-like particle vaccines.

关键词： Human papillomavirus capsid protein Helix-5 L1 pentamer

A pH-dependent molecular switch for virion uncoating

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protein & Cell 2014年第9期5卷 653-654页

作者： Satoshi Koike Neurovirology Project Tokyo Metropolitan Institute of Medical Science 2-1-6 Kamikitazawa Setagaya-ku Tokyo 156-8506Japan

Enterovirus 71, belonging to human enterovirus speCies A in the genus Enterovirus of the family Picornaviridae, is one of the main causative agents of hand-foot-mouth disease. It can also cause severe neurological diseases such as acute encephalitis, polio-like paralysis, and neurogenic pulmonary edema, and it has become a serious public health concern especially in the Asia-Pacific region.

关键词： capsid protein EV71 Infection Lysosomal Compartment Neurogenic Pulmonary Edema Native Virion