Journal of Microbiology

Review

Coronavirus enzyme inhibitors-experimentally proven natural compounds from plants: Junsoo Park , Rackhyun Park , Minsu Jang , Yea-In Park , Yeonjeong Park; J. Microbiol. 2022;60(3):347-354. Published online January 28, 2022; DOI: https://doi.org/10.1007/s12275-022-1499-z

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Coronavirus disease (COVID-19) can cause critical conditions that require efficient therapeutics. Several medicines are derived from plants, and researchers are seeking natural compounds to ameliorate the symptoms of COVID-19. Viral enzymes are popular targets of antiviral medicines; the genome of coronaviruses encodes several enzymes, including RNAdependent RNA polymerase and viral proteases. Various screening systems have been developed to identify potential inhibitors. In this review, we describe the natural compounds that have been shown to exert inhibitory effects on coronavirus enzymes. Although computer-aided molecular structural studies have predicted several antiviral compound candidates, the current review focuses on experimentally proven natural compounds.

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Eupatin, a Flavonoid, Inhibits Coronavirus 3CL Protease and Replication
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Structural Insights into Plasticity and Discovery of Flavonoid Allosteric Inhibitors of Flavivirus NS2B–NS3 Protease
Marielena Vogel Saivish, Gabriela de Lima Menezes, Vivaldo Gomes da Costa, Liliane Nebo, Gislaine Celestino Dutra da Silva, Carolina Colombelli Pacca, Rafael Elias Marques, Maurício Lacerda Nogueira, Roosevelt Alves Da Silva
Biophysica.2023; 3(1): 71. CrossRef
Plants as Biofactories for Therapeutic Proteins and Antiviral Compounds to Combat COVID-19
Corbin England, Jonathan TrejoMartinez, Paula PerezSanchez, Uddhab Karki, Jianfeng Xu
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Computational investigation of natural compounds as potential main protease (Mpro) inhibitors for SARS-CoV-2 virus
Chirag N. Patel, Siddhi P. Jani, Sivakumar Prasanth Kumar, Krunal M. Modi, Yogesh Kumar
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Two years of COVID-19 pandemic: where are we now?
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Journal of Microbiology.2022; 60(3): 235. CrossRef
Identification of SARS-CoV-2 Main Protease Inhibitors from a Library of Minor Cannabinoids by Biochemical Inhibition Assay and Surface Plasmon Resonance Characterized Binding Affinity
Chang Liu, Tess Puopolo, Huifang Li, Ang Cai, Navindra P. Seeram, Hang Ma
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Computational Approaches in the Discovery and Development of Therapeutic and Prophylactic Agents for Viral Diseases
Anand Gaurav, Neetu Agrawal, Mayasah Al-Nema, Vertika Gautam
Current Topics in Medicinal Chemistry.2022; 22(26): 2190. CrossRef

Journal Article

Human cytomegalovirus IE86 protein aa 136–289 mediates STING degradation and blocks the cGAS-STING pathway: Jun-Kyu Lee , Jung-Eun Kim , Bang Ju Park , Yoon-Jae Song; J. Microbiol. 2020;58(1):54-60. Published online January 2, 2020; DOI: https://doi.org/10.1007/s12275-020-9577-6

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Abstract

We previously reported that human cytomegalovirus (HCMV) 86 kDa immediate-early 2 gene product (IE86) promotes proteasome-dependent degradation of STING. In the present study, we determined the specific residues of IE86 responsible for STING degradation using a STING-firefly luciferase fusion protein expression system for quantitative measurement of STING protein levels. IE86 amino acids (aa) 136–289 were sufficient to promote STING degradation and further induced down-regulation of 2􍿁3􍿁-cyclic GMP-AMP (cGAMP)-mediated IFN-β promoter activation. Interestingly, transactivation domains (TAD) of the IE86 protein located at the N- and C-termini were required for down-regulation of Toll/interleukin-1 receptor (TIR) domain-containing adaptor- inducing interferon β (IFN-β) (TRIF)-mediated IFN-β- and p65/RelA-induced NF-κB-dependent promoter activation while amino acids (aa) 136–289 had no significant effects. Our collective data suggest that the IE86 protein utilizes the aa 136–289 region to promote STING degradation and inhibit the cGAS-STING pathway.

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Research Support, Non-U.S. Gov'ts

Requirement of the N-terminal residues of human cytomegalovirus UL112-113 proteins for viral growth and oriLyt-dependent DNA replication: Young-Eui Kim , Mi Young Park , Kyeong Jin Kang , Tae Hee Han , Chan Hee Lee , Jin-Hyun Ahn; J. Microbiol. 2015;53(8):561-569. Published online July 31, 2015; DOI: https://doi.org/10.1007/s12275-015-5301-3

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Abstract

The UL112-113 region of the human cytomegalovirus (HCMV) genome encodes four phosphoproteins of 34, 43, 50, and 84 kDa that promote viral DNA replication. Co-transfection assays have demonstrated that self-interaction of these proteins via the shared N-termini is necessary for their intranuclear distribution as foci and for the efficient relocation of a viral DNA polymerase processivity factor (UL44) to the viral replication sites. However, the requirement of UL112- 113 N-terminal residues for viral growth and DNA replication has not been fully elucidated. Here, we investigated the effect of deletion of the N-terminal regions of UL112- 113 proteins on viral growth and oriLyt-dependent DNA replication. A deletion of the entire UL112 region or the region encoding the 25 N-terminal amino-acid residues from the HCMV (Towne strain) bacmid impaired viral growth in bacmid-transfected human fibroblast cells, indicating their requirement for viral growth. In co-immunoprecipitation assays using the genomic gene expressing the four UL112- 113 proteins together, the 25 N-terminal amino-acid residues were found to be necessary for stable expression of UL112- 113 proteins and their self-interaction. These residues were also required for efficient binding to and relocation of UL44, but not for interaction with IE2, an origin-binding transcription factor. In co-transfection/replication assays, replication of the oriLyt-containing plasmid was promoted by expression of intact UL112-113 proteins, but not by the expression of 25-amino-acid residue-deleted proteins. Our
results
demonstrate that the 25 N-terminal amino-acid residues of UL112-113 proteins that mediate self-interaction contribute to viral growth by promoting their binding to UL44 and the initiation of oriLyt-dependent DNA replication.

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Insights into the Transcriptome of Human Cytomegalovirus: A Comprehensive Review
Janine Zeng, Di Cao, Shaomin Yang, Dabbu Kumar Jaijyan, Xiaolian Liu, Songbin Wu, Ruth Cruz-Cosme, Qiyi Tang, Hua Zhu
Viruses.2023; 15(8): 1703. CrossRef
The human cytomegalovirus decathlon: Ten critical replication events provide opportunities for restriction
Declan L. Turner, Rommel A. Mathias
Frontiers in Cell and Developmental Biology.2022;[Epub] CrossRef
Degradation of SAMHD1 Restriction Factor Through Cullin-Ring E3 Ligase Complexes During Human Cytomegalovirus Infection
Seokhwan Hyeon, Myoung Kyu Lee, Young-Eui Kim, Gwang Myeong Lee, Jin-Hyun Ahn
Frontiers in Cellular and Infection Microbiology.2020;[Epub] CrossRef
Primary lymphocyte infection models for KSHV and its putative tumorigenesis mechanisms in B cell lymphomas
Sangmin Kang, Jinjong Myoung
Journal of Microbiology.2017; 55(5): 319. CrossRef
Differential Requirement of Human Cytomegalovirus UL112-113 Protein Isoforms for Viral Replication
Tim Schommartz, Jiajia Tang, Rebekka Brost, Wolfram Brune, Klaus Frueh
Journal of Virology.2017;[Epub] CrossRef

Allelic MHC Class I Chain Related B (MICB) Molecules Affect the Binding to the Human Cytomegalovirus (HCMV) Unique Long 16 (UL16) Protein: Implications for Immune Surveillance: Kanya Klumkrathok , Amonrat Jumnainsong , Chanvit Leelayuwat; J. Microbiol. 2013;51(2):241-246. Published online April 27, 2013; DOI: https://doi.org/10.1007/s12275-013-2514-1

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Abstract: Unique long 16 (UL16) is a viral glycoprotein produced in a host cell infected with human cytomegalovirus (HCMV). It down regulates surface expression of MICB, one of the NKG2D ligands, by forming stable intracellular complexes and retained in the endoplasmic reticulum. Down expression of MICB renders cells less susceptible to NK cell lysis via the NKG2D receptor. Diverse UL16 sequences were identified from different strains of HCMV. MICB is known to be polymorphic. It is not known whether these polymorphisms affect the interactions between these molecules leading to alteration of the immune surveillance of HCMV. The soluble Fc fusion variant UL16 proteins from four laboratory and clinical isolates (AD169, Toledo, PH, and TR) were produced. Four allelic MICB alleles (008, 003, 004, and 00502) were cloned and stable cell lines expressing these MICB alleles were produced. The binding activities of variant UL16 to allelic MICB proteins were determined by flow cytometry. The variants of UL16 proteins did not affect the binding activities to allelic MICB proteins. However, diverse MICB alleles differentially bound UL16. We found that MICB*008 which contains methionine and asparagine at the amino acid positions 98 and 113, respectively, in the alpha 2 domain showed decreased binding activities to UL16 when compared to MICB*003, 004, and MICB*00502 containing isoleucine and aspartic acid, respectively. This finding may imply that MICB*008 is a protective allele and involved in the immune surveillance of HCMV infected patients.

Nitric oxide in human cytomegalovirus replication and gene expression: Lee, Jee Yeon , Lee, Chan Hee; J. Microbiol. 1997;35(2):152-157.

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Abstract: Infection of human fibroblast (HF) cells with human cytomegalovirus (HCMV) result in changes in the intracellular level of second messengers. Since nitric oxide (NO) production has been known to be related with other second messengers, it is probable that HCMV infection of HF cells may involve NO. To test this possibility, the amount of NO was measured following HCMV infection but we were not able to detect significant change in the production of NO. Exogenous addition of NO generators such as sodium nitroprusside (SNP) or S-nitroso-N-a-cetylpenicillamine (SNAP) immediately after HCMV infection, however, inhibited virus multiplication. Furthermore, immunoblot experiment using monoclonal antibody to HCMV major immediate early (MIE) proteins or CAT assay using pCMVIE/CAT (plasmid containing CAT gene driven by HCMV MIE promoter) revealed that SNP or SNAP blocked the MIE gene expression. SNP was more effective than SNAP in hibiting HCMV multiplication or MIE gene expression. SNP produced more NO than SNAP in inhibiting HCMV multiplication or MIE gene expression. SNP produced more NO than SNAP. Although the mechanism for the inhibition of HCMV multiplication and MIE gene expression by NO is still elusive some correlation with NO-mediated inhibition of HCMV-induced increase in cytosolic free Ca^2+ concentration ([Ca^2+]) was observed. The increase of [Ca^2+] following HCMV infection was inhibited by SNP, and less effectively by SNAP. Raising [Ca^2+ with bromo-A23187 partially reversed the SNP block of MIE gene expression. Thus, there appear to e some relationships among NO. [Ca^2+], and HCMV MIE gene expression.

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