scholarly journals Decoy Receptor Interactions as Novel Drug Targets against EKC-Causing Human Adenovirus

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 242 ◽  
Author(s):  
Naresh Chandra ◽  
Lars Frängsmyr ◽  
Niklas Arnberg
Keyword(s):  
Drug Targets ◽  
Antiviral Drug ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Antiviral Effect ◽  
Epidemic Keratoconjunctivitis ◽  
Virus Binding ◽  
Decoy Receptor ◽  
Decoy Receptors ◽  
Approved Drugs

Epidemic keratoconjunctivitis (EKC) is a severe ocular disease and can lead to visual impairment. Human adenovirus type-37 (HAdV-D37) is one of the major causative agents of EKC and uses sialic acid (SA)-containing glycans as cellular receptors. Currently, there are no approved antivirals available for the treatment of EKC. Recently, we have reported that sulfated glycosaminoglycans (GAGs) bind to HAdV-D37 via the fiber knob (FK) domain of the viral fiber protein and function as decoy receptors. Based on this finding, we speculated that GAG-mimetics may act as artificial decoy receptors and inhibit HAdV-D37 infection. Repurposing of approved drugs to identify new antivirals has drawn great attention in recent years. Here, we report the antiviral effect of suramin, a WHO-approved drug and a widely known GAG-mimetic, against HAdV-D37. Commercially available suramin analogs also show antiviral effects against HAdV-D37. We demonstrate that suramin exerts its antiviral activity by inhibiting the attachment of HAdV-D37 to cells. We also reveal that the antiviral effect of suramin is HAdV species-specific. Collectively, in this proof of concept study, we demonstrate for the first time that virus binding to a decoy receptor constitutes a novel and an unexplored target for antiviral drug development.

scholarly journals Sulfated Glycosaminoglycans as Viral Decoy Receptors for Human Adenovirus Type 37

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 247 ◽  
Author(s):  
Naresh Chandra ◽  
Yan Liu ◽  
Jing-Xia Liu ◽  
Lars Frängsmyr ◽  
Nian Wu ◽  
...  
Keyword(s):  
Plasma Membranes ◽  
Therapeutic Potential ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Sodium Chlorate ◽  
Target Cells ◽  
Epidemic Keratoconjunctivitis ◽  
Virus Binding ◽  
Surface Plasmon Resonance Analysis ◽  
Decoy Receptors

Glycans on plasma membranes and in secretions play important roles in infection by many viruses. Species D human adenovirus type 37 (HAdV-D37) is a major cause of epidemic keratoconjunctivitis (EKC) and infects target cells by interacting with sialic acid (SA)-containing glycans via the fiber knob domain of the viral fiber protein. HAdV-D37 also interacts with sulfated glycosaminoglycans (GAGs), but the outcome of this interaction remains unknown. Here, we investigated the molecular requirements of HAdV-D37 fiber knob:GAG interactions using a GAG microarray and demonstrated that fiber knob interacts with a broad range of sulfated GAGs. These interactions were corroborated in cell-based assays and by surface plasmon resonance analysis. Removal of heparan sulfate (HS) and sulfate groups from human corneal epithelial (HCE) cells by heparinase III and sodium chlorate treatments, respectively, reduced HAdV-D37 binding to cells. Remarkably, removal of HS by heparinase III enhanced the virus infection. Our results suggest that interaction of HAdV-D37 with sulfated GAGs in secretions and on plasma membranes prevents/delays the virus binding to SA-containing receptors and inhibits subsequent infection. We also found abundant HS in the basement membrane of the human corneal epithelium, which may act as a barrier to sub-epithelial infection. Collectively, our findings provide novel insights into the role of GAGs as viral decoy receptors and highlight the therapeutic potential of GAGs and/or GAG-mimetics in HAdV-D37 infection.

scholarly journals Notes from the Field: Epidemic Keratoconjunctivitis Outbreak Associated with Human Adenovirus Type 8 — U.S. Virgin Islands, June–November 2016

2017 ◽  
Vol 66 (30) ◽  
pp. 811-812 ◽  
Author(s):  
Marie E. Killerby, ◽  
Matthew J. Stuckey, ◽  
Irene Guendel, ◽  
Senthilkumar Sakthivel, ◽  
Xiaoyan Lu, ◽  
...  
Keyword(s):  
Human Adenovirus ◽  
Adenovirus Type ◽  
Virgin Islands ◽  
Epidemic Keratoconjunctivitis

scholarly journals FDA Approved Drugs Efavirenz, Tipranavir, and Dasabuvir Inhibit Replication of Multiple Flaviviruses In Vitro

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 6
Author(s):  
Michal Stefanik ◽  
Fortunatus C Ezebuo ◽  
Jan Haviernik ◽  
Ikemefuna C. Uzochukwu ◽  
Martina Fojtikova ◽  
...  
Keyword(s):  
Yellow Fever Virus ◽  
Antiviral Drug ◽  
Antiviral Effect ◽  
Vero Cells ◽  
Significant Inhibition ◽  
Structural Protein ◽  
Inhibition Effect ◽  
Tick Borne Encephalitis Virus ◽  
Approved Drugs

Arthropod-borne flaviviruses such as tick-borne encephalitis virus (TBEV), West Nile virus (WNV), Zika virus (ZIKV), Dengue virus (DENV), and yellow fever virus (YFV) cause several serious life-threatening syndromes (encephalitis, miscarriages, paralysis, etc.). No effective antiviral therapy against these viruses has been approved yet. We selected, via in silico modeling, 12 U.S. Food and Drug Administration (FDA)-approved antiviral drugs (paritaprevir, dolutegravir, raltegravir, efavirenz, elvitegravir, tipranavir, saquinavir, dasabuvir, delavirdine, maraviroc, trifluridine, and tauroursodeoxycholic acid) for their interaction with ZIKV proteins (NS3 helicase and protease, non-structural protein 5 (NS5) RNA-dependent RNA polymerase, and methyltransferase). Only three of them were active against ZIKV, namely, dasabuvir (ABT-333), efavirenz, and tipranavir. These compounds inhibit virus replication of ZIKV (MR-766 and Paraiba_01) in Vero cells; therefore, we tested these compounds against other medically important flaviviruses WNV (13-104 and Eg101) and TBEV (Hypr). Dasabuvir was originally developed as an antiviral drug against hepatitis C virus (HCV); tipranavir and efavirenz are used for treating human immunodeficiency virus (HIV) infection. The antiviral effects of efavirenz, tipranavir, and dasabuvir were tested for ZIKV in HUH-7, astrocytes (HBCA), and UKF-NB-4 cells, where we also identified a significant inhibition effect of these compounds. For Vero cells, efavirenz inhibited all investigated viruses with EC50 ranging from 9.70 to 29.26 µM; the tipranavir inhibition effect was from 16.19 (WNV 13-104) to 27.47 µM (TBEV), while the strongest and most robust antiviral effect was demonstrated in the case of dasabuvir (EC50 values ranging from 9.09 (TBEV) to 10.85 µM (WNV 13-104)). These results warrant further research of these drugs, either individually or in combination, as possible pan-flavivirus inhibitors.

scholarly journals Five Cases of Epidemic Keratoconjunctivitis Due to Human Adenovirus Type 85 in Fukushima, Japan

2020 ◽  
Vol 73 (4) ◽  
pp. 316-319
Author(s):  
Hisatoshi Kaneko ◽  
Nozomu Hanaoka ◽  
Masami Konagaya ◽  
Masaaki Kobayashi ◽  
Hisashi Nakagawa ◽  
...  
Keyword(s):  
Human Adenovirus ◽  
Adenovirus Type ◽  
Epidemic Keratoconjunctivitis

Coronavirus Disease 2019: Virology and Drug Targets

2020 ◽  
Vol 20 ◽  
Author(s):  
Praveen Thaggikuppe Krishnamurthy
Keyword(s):  
High Throughput Screening ◽  
Drug Targets ◽  
Vaccine Development ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
Structural Proteins ◽  
Current Status ◽  
Approved Drugs ◽  
Viral Target ◽  
Fda Approved Drugs

: The Coronavirus Disease 2019, a pandemic caused by novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is seriously affecting global health and the economy. As the vaccine development takes time, the current research is focused on repurposing FDA approved drugs against the viral target proteins. This review discusses the current understanding of SARS-CoV-2 virology, its target structural proteins (S- glycoprotein), non-structural proteins (3- chymotrypsin-like protease, papain-like protease, RNA-dependent RNA polymerase, and helicase) and accessory proteins, drug discovery strategies (drug repurposing, artificial intelligence, and high-throughput screening), and the current status of antiviral drug development.

scholarly journals Analysis of the complete genome sequence of epidemic keratoconjunctivitis-related human adenovirus type 8, 19, 37 and a novel serotype

2009 ◽  
Vol 90 (6) ◽  
pp. 1471-1476 ◽  
Author(s):  
Hisatoshi Kaneko ◽  
Tomohiro Iida ◽  
Hiroaki Ishiko ◽  
Takeshi Ohguchi ◽  
Toshihide Ariga ◽  
...  
Keyword(s):  
Genome Sequence ◽  
Complete Genome Sequence ◽  
Complete Genome ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Clinical Strain ◽  
Epidemic Keratoconjunctivitis ◽  
Hypervariable Regions ◽  
Distinct Cluster ◽  
Loop 2

We determined the complete genome sequence of epidemic keratoconjunctivitis (EKC)-related human adenoviruses (HAdVs). We analysed a total of 12 HAdV strains; three prototype strains and two HAdV-8, three HAdV-19 and three HAdV-37 clinical isolates from EKC patients in Japan, and one novel serotype of HAdV. Genome organization of these serotypes was identical to those of the recently determined HAdV-19 and HAdV-37. The identities of the whole genome were over 99 % among strains from the same serotype, except for HAdV-19p, which is not associated with conjunctivitis, resulting in the formation of a distinct cluster in the phylogenetic analysis. The penton, loop 1 and loop 2 of hexon, early region 3 (E3) and fiber were hypervariable regions between serotypes. Results suggest that the HAdV-19 clinical strain is a recombinant of HAdV-19p-like and HAdV-37-like strains, and that the acquisition of the penton, E3 or fiber may be related to ocular tropism.

scholarly journals Recombination analysis of intermediate human adenovirus type 53 in Japan by complete genome sequence

2011 ◽  
Vol 92 (6) ◽  
pp. 1251-1259 ◽  
Author(s):  
Hisatoshi Kaneko ◽  
Koki Aoki ◽  
Susumu Ishida ◽  
Shigeaki Ohno ◽  
Nobuyoshi Kitaichi ◽  
...  
Keyword(s):  
Complete Genome ◽  
Phylogenetic Analyses ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Penton Base ◽  
Recombination Detection Program ◽  
Genome Sequences ◽  
Epidemic Keratoconjunctivitis ◽  
Detection Program ◽  
Recombination Breakpoints

Human adenovirus type 53 (HAdV-53) has commonly been detected in samples from epidemic keratoconjunctivitis (EKC) patients in Japan since 1996. HAdV-53 is an intermediate virus, containing hexon-chimeric, penton base and fiber structures similar to HAdV-22 and -37, HAdV-37 and HAdV-8, respectively. HAdV-53-like intermediate strains were first isolated from EKC samples in Japan in the 1980s. Here, the complete genome sequences of three such HAdV-53-like intermediate strains (870006C, 880249C and 890357C) and four HAdV-53 strains were determined, and their relationships were analysed. The seven HAdV strains were classified into three groups, 870006C/880249C, 890357C and the four HAdV-53 strains, on the basis of phylogenetic analyses of the partial and complete genome sequences. HAdV strains within the same group showed the highest nucleotide identities (99.87–100.00 %). Like HAdV-53, the hexon loop 1 and 2 regions of 870006C, 880249C and 890357C showed the highest identity with HAdV-22. However, these strains did not show a hexon-chimeric structure similar to HAdV-22 and -37, or a penton base similar to HAdV-37. The fiber genes of 870006C and 880249C were identical to that of HAdV-37, but not HAdV-8. Thus, the three intermediate HAdVs isolated in the 1980s were similar to each other but not to HAdV-53. The recombination breakpoints were inferred by the Recombination Detection Program (rdp) using whole-genome sequences of these seven HAdV and of 12 HAdV-D strains from GenBank. HAdV-53 may have evolved from intermediate HAdVs circulating in the 1980s, and from HAdV-8, -22 and -37, by recombination of sections cut at the putative breakpoints.

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