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Discovery of N-benzyl hydroxypyridone carboxamides as a novel and potent antiviral chemotype against human cytomegalovirus (HCMV)

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1671-1684页

作者： Sameera Senaweera Tiffany C.Edwards Jayakanth Kankanala Yan Wang Rajkumar Lalji Sahani Jiashu Xie Robert J.Geraghty Zhengqiang Wang Center for Drug Design College of PharmacyUniversity of MinnesotaMinneapolisMN 55455USA Translational Medicine R&D Center Shenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China

Current drugs for treating human cytomegalovirus(HCMV)infections are limited by resistance and treatment-associated toxicities.In developing mechanistically novel HCMV antivirals,we discovered an N-benzyl hydroxypyridone carboxamide antiviral hit(8a)inhibiting HCMV in submicromolar range.We describe herein the structure–activity relationship(SAR)for 8a,and the characterization of potent analogs for cytotoxicity/cytostatic property,the preliminary mechanism of action,and the absorption,distribution,metabolism and excretion(ADME)properties.The SAR revealed a few pharmacophore features conferring optimal antiviral profile,including the 5-OH,the N-1 benzyl,at least one–CH_(2)−in the linker,and a di-halogen substituted phenyl ring in the amide moiety.In the end,we identified numerous analogs with sub-micromolar antiviral potency and good selectivity index.The preliminary mechanism of action characterization used a pUL89-C biochemical endonuclease assay,a virus entry assay,a time-of-addition assay,and a compound withdrawal assay.ADME profiling measuring aqueous solubility,plasma and liver microsomal stability,and parallel artificial membrane permeability assay(PAMPA)permeability demonstrated largely favorable drug-like properties.Together,these studies validate the N-benzyl hydroxypyridone carboxamide as a viable chemotype for potent and mechanistically distinct antivirals against HCMV.

关键词： human cytomegalovirus N-Benzyl hydroxypyridone carboxamides Structureeactivity relationship Mechanism of action

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Classical and non-classical MHC I molecule manipulation by human cytomegalovirus： so many targets--but how many arrows in the quiver？

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Cellular & Molecular Immunology 2015年第2期12卷 139-153页

作者： Anne Halenius Carolin Gerke Hartmut Hengel Institute of Virology University Medical Center Albert-Ludwig-University Freiburg Freiburg Germany

Major mechanisms for the recognition of pathogens by immune cells have evolved to employ classical and non-classical major histocompatibility complex class I （MHC I） molecules. Classical MHC I molecules present antigenic peptide ligands on infected cells to CD8＋ T cells, whereas a key function for non-classical MHC I molecules is to mediate inhibitory or activating stimuli in natural killer （NK） cells. The structural diversity of MHC I puts immense pressure on persisting viruses, including cytomegaloviruses. The very large coding capacity of the human cytomegalovirus allows it to express a whole arsenal of immunoevasive factors assigned to individual MHC class I targets. This review summarizes achievements from more than two decades of intense research on how human cytomegalovirus manipulates MHC I molecules and escapes elimination by the immune system.

关键词： antigen presentation CD8＋ T cells NK cells human cytomegalovirus immune evasion KIR

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Association of TRIM22 with the type 1 interferon response during primary human cytomegalovirus infection in THP-1 macrophages

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BIOCELL 2019年第4期43卷 285-291页

作者： WEI LI HUIHUI GAO RAN TAO LIFANG LIU SHIQIANG SHANG Department of Clinical Laboratory the Children’s HospitalZhejiang University School of MedicineNational Clinical Research Center For Child HealthHangzhou310052China

As a response factor of interferon,tripartite motif(TRIM)22 was reported to exert antiviral activity against viruses.In this study,THP-1 macrophages were infected with human cytomegalovirus(HCMV)to establish the HCMV lytic infection model.The mRNA levels of interleukin-6(IL-6),tumor necrosis factor-alpha(TNF-α)and interferonbeta(IFN-β)were significantly up-regulated in THP-1 macrophages at different infection time and titers.Moreover,for the first time,upregulation of TRIM22 expression was found during HCMV infection at both mRNA and protein levels in THP-1 macrophages.Furthermore,IFN-β could induce TRIM22 expression in THP-1 macrophages or HCMV infected THP-1 macrophages.Depletion of TRIM22 increased replication activity of HCMV with increasing of HCMV titers and HCMV proteins.In conclusion,it is the first report that HCMV can induce TRIM22 activation through IFN-β signaling and TRIM22 can suppress replication of HCMV in THP-1 macrophages.

关键词： human cytomegalovirus TRIM22 IFN-βReplication

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Effect of Baicalein on the Expression of VIP in Extravillous Cytotrophoblasts Infected with human cytomegalovirus In Vitro

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2013年第3期33卷 406-411页

作者：乔媛方建国肖娟刘涛刘静张艳丽陈素华 Department of Obstetrics and Gynecology Tongji HospitalTongji Medical CollegeHuazhong University of Science and Technology Department of Pharmacy Tongji HospitalTongji Medical CollegeHuazhong University of Science and Technology Department of Obstetrics and Gynecology Tai'an City Central Hospital

Summary： This paper aimed to study the ability of baicalein to block human cytomegalovirus （HCMV） infection in extravillous cytotrophoblasts （EVT） and its effect on the vasoactive intestinal peptide （VIP） expression in HCMV-infected EVT in vitro. A human trophoblast cell line （HPT-8） was chosen in this study. HCMV with 100 TCIDs0was added into culture medium to infect HPT-8 cells, and then HCMV pp65 antigen was assayed by immunofluorescence staining. The infection status was determined by vi- rus titration. Real-time quantitative polymerase chain reaction （qRT-PCR） was used to detect virus DNA load in the infected cells. The expression of VIP mRNA and protein in the infected cells was measured by qRT-PCR, immunocytochemistry and Western blotting. Concentration of VIP secreted in supernatants was determined by ELISA. Red-stained HCMV pp65 antigens were found in infected HPT-8 cells 48 h after infection. HCMV replicated in large quantity in infected HPT-8 cells 4 days after infection, reaching a peak at day 6 post-infection. After treatment with baicalein, virus DNA load in in- fected HPT-8 cells was decreased （P〈0.05）, and the levels of VIP mRNA and protein, and the concen- tration were raised to the normal （P〉0.05）. Our study suggested that baicalein exerts a positive effect on the VIP expression in HCMV-infected EVT at maternal-fetal interface.

关键词： baicalein human cytomegalovirus extravillous cytotrophoblasts vasoactive intestinal pep- tide

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Effect of human cytomegalovirus on Invasive Capability of Early Pregnant Extravillous Cytotrophoblasts

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2011年第6期31卷 819-823页

作者：刘涛郑晓菲陈娟娟王楠肖娟张丹丹尹宗智李伟陈素华 Department of Obstetrics and Gynecology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Department of Obstetrics and Gynecology Tai'an Central Hospital Department of Information Center Tai'an Central Hospital

The effect of human cytomegalovirus （HCMV） on invasive capability of early pregnant extravillous cytotrophoblasts （EVTs） was investigated in vitro. Primary EVTs were obtained by complex phosphoesterasum digestion and gradient centrifugation from villous tissue aseptically taken from healthy pregnant women. Cytokeratin7 （CK7）, vimentin （Vim） and cerbB-2 were immunocytochemically detected to identify source of cells, and HCMVpp65 antigen was assayed to determine the infection state of primary EVTs by immunocytochemical staining. The EVTs were divided into two groups： control group and HCMV group, and the expression of c-erbB-2, matrix metalloproteinase-2 （MMP-2） and MMP-9 proteins was detected in two groups by immunocytochemistry and Western blotting. Enzymic activity changes of MMP-2 and MMP-9 were tested by gelatin zymography in primary EVTs infected with HCMV. The invasion of primary EVTs was detected by cell invasion assay in vitro after they were infected by HCMV. The cell source identification showed that the cells obtained were highly-pure primary EVTs, and primary EVTs could be infected by HCMV. Primary EVTs could express c-erbB-2, MMP-2 and MMP-9 proteins, and as compared with control group, the protein expression was decreased significantly in HCMV groups （P〈0.05）. Primary EVTs could secrete active MMP-2 and MMP-9 in vitro, and the activity of two MMPs was decreased sig- nificantly in HCMV groups （P〈0.05）. The in vitro cell invasion assay showed that the number of primary EVTs permeating Matrigel in HCMV group was decreased （P〈0.05）. We are led to conclude that HCMV can infect primary EVTs and inhibit their invasion capability, suggesting that the im- paired EVT＇s invasion capability might be related to the abnormal expression of c-erbB-2, MMP-2 and MMP-9 proteins.

关键词： human cytomegalovirus extravillous cytotrophoblast c-erbB-2 MMP-2 MMP-9 invasion

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Effect of human cytomegalovirus Infection on Nerve Growth Factor Expression in human Glioma U251 Cells

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Biomedical and Environmental Sciences 2009年第4期22卷 354-358页

作者： HAI-TAO WANG BIN WANG ZHI-JUN LIU ZHI-QIANG BAI LING LI HAI-YAN LIU DONG-MENG QIAN ZHI-YONG YAN XU-XIA SONG Department of Microbiology Qingdao Medical College and Key Laboratory of Medicine and Biotechnology of Qingdao Qingdao University Medical College Qingdao 266071 Shandong China Qingdao Center for Disease Control and Prevention Qingdao 266033 Shandong China LRB 270E University of Massachusetts Medical School Worcester MA. 01605 USA

Objective To explore the change of endogenic nerve growth factor （NGF） expression in human glioma cells infected with human cytomegalovirus （HCMV）. Methods U251 cells were cultured in RPMI 1640 culture medium and infected with HCMV AD 169 strain in vitro to establish a cell model of viral infection. Morphologic changes of U251 cells were observed under inverted microscope before and after infection with HCMV. Expression of NGF gene and protein of cells was detected by RT-PCR and Western blotting before and after infection with HCMV. Results The cytopathic effects of HCMV-infected cells appeared on day 5 after infection. However, differential NGF expression was evident on day 7. NGF expression was decreased significantly in U251 cells on day 7 after infection in comparison with control group （P〈0.05）. Conclusion HCMV can down-regulate endogenous NGF levels in human glioma cell line U251.

关键词： human cytomegalovirus U251 cells Nerve growth factor

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Recombinant human IgG antibodies against human cytomegalovirus

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Biomedical and Environmental Sciences 2008年第5期21卷 372-380页

作者： TAO DUAN XIAO-FANG WANG SHU-YUAN XIAO SHU-YAN GU AND MI-FANG LIANG Institute for Viral Disease Control and Prevention Chinese Center for Disease Control and Prevention Beijing 100052 China Department of Pathology and Center for Biodefence and Emerging Infectious Diseases University of Texas Medical Branch Galveston Texas 77555-0609. USA

Objective To study the passive immunization with human monoclonal antibodies as for prophylaxis of human cytomegalovirus （HCMV） infection. Methods Fab monoclonal antibodies to HCMV were recovered by repertoire cloning of mRNA from a HCMV infected individual. Antigen binding specificity, CDR sequence of VH and VL and neutralizing activity on HCMV AD169 stain were analyzed in vitro. The light and heavy chain Fd fragment genes of Fab antibodies were further cloned into a recombinant baculovirus expression vector pAC-K-Fc to express intact IgG. Secreted products were purified with affinity chromatography using protein G. Results SDS-PAGE and Western blot confirmed the expression of the intact IgG. Immuno-blotting and -precipitation were used to identify HCMV proteins. One Fab monoclonal antibody recognized a conformational HCMV protein. Conclusion IgG antibodies can neutralize the HCMV AD169 strain efficiently at a titer of 2.5 μg/mL and may prove valuable for passive immunoprophylaxis against HCMV infection in humans.

关键词： human cytomegalovirus human engineering antibody Phage display Recombinant baculovirus expression

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Modulation of HLA Expression in human cytomegalovirus Immune Evasion

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Cellular & Molecular Immunology 2007年第2期4卷 91-98页

作者： Aifen Lin Huihui Xu Weihua Yan Medical Research Center Wenzhou Medical College Affiliated Taizhou Hospital of Zhejiang Province Linhai Zhejiang 317000 China

human cytomegalovirus （hCMV） has evolved multiple mechanisms to escape the host immune recognition and innate or adaptive immune responses. Among them, hCMV has developed strategies to modulate the expression and/or function of human leukocyte antigens （HLAs）, including by encoding series of infection stage-dependent hCMV proteins to detain and destroy the expression of HLA molecules on the surface of infected cells. This disturbs the antigen presentation and processing, by encoding MHC class I homologues or selective up-regulation of particular HLA class I molecules binding to NK cell inhibitory receptors, and by encoding specific ligand antagonists to interfere with NK cell activating receptors. Here we discussed the molecular mechanisms utilized by the hCMV to alter the formation, transportation and expression of HLA antigens on the infected cell surface. The knowledge about hCMV modulating HLA expression could benefit us to further understand the pathogenesis of viral diseases and may eventually develop novel effective immunotherapies to counteract viral infections and viral associated diseases.

关键词： HLA human cytomegalovirus NK cell T lymphocyte

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Sequence variability of human cytomegalovirus UL143 in low-passage clinical isolates

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Chinese Medical Journal 2006年第5期119卷 397-402页

作者： HE Rong RUAN Qiang QI Ying MA Yan-ping HUANG Yu-jing SUN Zheng-rong JI Yao-hua Virus Laboratory Second Affiliated Hospital China Medical University Shenyang 110004 China

Background human cytomegalovirus （HCMV） infects a number of organs and tissues in vivo. The different symptoms and tissue tropisms of HCMV infection perhaps result from genetic polymorphism. A new region of DNA containing at least 19 open reading frames （ORFs）（denoted UL133 to 151） was found in the low-passage HCMV clinical strain, Toledo, and several other low-passage clinical isolates, but not present in the HCMV laboratory strain, AD169. One of these genes, UL143, was studied to explore the sequence variability of UL143 ORF in HCMV clinical isolates and examine the possible association between gcne variability and the outcome of HCMV infection. Methods The UL143 gone of the strains obtained from suspected congenitally HCMV-infectcd infants was amplified by polymerase chain reaction （PCR） and sequenced. Results Nineteen sequences of the strains were divided into 2 major groups, G1（n=16） and G2（n=3）. All of the sequences had frame-shift mutation compared to Toledo. Nucleotide polymorphisms conferred substantial amino acid substitutions when compared with Toledo. All 16 UL143 putative proteins of the strains in G1 had a new myristylation site and loss of two PKC sites owing to missense mutations. No convincing relationships were observed between the presence of HCMV disease and the UL143 sequence group. Conclusions HCMV-UL143 existed in low passage isolates. Sequence variability caused by frame -shift mutation was found in all HCMV clinical strains. No obvious linkage was observed between UL143 polymorphisms and the outcome of suspected congenital HCMV infection.

关键词： human cytomegalovirus UL 143 gene polymorphism

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Evaluation on Clinical Application of Three Testing Methods for human cytomegalovirus Infection in Pregnancy

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2003年第2期23卷 192-194页

作者：曾万江闻良珍陈素华凌霞珍 Department of Obstetrics and Gynecology Tongji HospitalTongji MedicalCollegeHuazhong University of Science and Technology Wuhan 430030

The value of ELISA, N-PCR and RT-PCR in clinical practice for pregnant women with HCMV infection was investigated. 5581 pregnant women were screened by ELISA. Among them, 100 cases were positive for IgM (group 1). 69 for both IgM and serous DNA (group 2) and 69 for both IgM and mRNA (group 3). The infectious status, maternal-fetal transmission and pregnancy outcome were monitored. It was demonstrated that the accordance rate of group 3 and group 2 with group 1 was 56. 25 % and 43. 75 % , respectively. The maternal-fetal transmission rate in the group 1, 2 and 3 was 19. 00 % , 40. 58 % and 46. 15 %, respectively, with a significant difference found between group 2, 3 and group 1 (P<0. 01). Incidence of spontaneous abortion, fetal death, fetal abnormality and neonatal death in group 1, 2 and 3 was 10. 00 %, 15. 94 % and 30. 77 %, respectively, and that of group 3, 2 was 4 and 2 times as much as that of group 1, respectively (OR = 4. 00, P<0. 001; OR=2. 343, P<005, respectively). It was concluded that HCMV-IgM(+) can only be considered as an screening indicator for pregnant women with HCMV infection, while IgM(+) combined with serous DNA( + ) or mRNA( + ) indicates active infection and has a high incidence of maternal-fetal transmission and abnormal pregnancy outcome.

关键词： human cytomegalovirus enzyme linked immunosorbent assay polymerase chain reaction : pregnancvaction pregnancy

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