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Article ; Online: Antiviral Strategies against Arthritogenic Alphaviruses

Rana Abdelnabi / Leen Delang

Microorganisms, Vol 8, Iss 1365, p

2020 Volume 1365

Abstract: Alphaviruses are members of the Togaviridae family that are mainly transmitted by arthropods such as mosquitoes. In the last decades, several alphaviruses have re-emerged, causing outbreaks worldwide. One example is the re-emergence of chikungunya virus ( ...

Abstract	Alphaviruses are members of the Togaviridae family that are mainly transmitted by arthropods such as mosquitoes. In the last decades, several alphaviruses have re-emerged, causing outbreaks worldwide. One example is the re-emergence of chikungunya virus (CHIKV) in 2004, which caused massive epidemics in the Indian Ocean region after which the virus dramatically spread to the Americas in late 2013. Besides CHIKV, other alphaviruses, such as the Ross River virus (RRV), Mayaro virus (MAYV), and Venezuelan equine encephalitis virus (VEEV), have emerged and have become a serious public health concern in recent years. Infections with the Old World alphaviruses (e.g., CHIKV, RRV) are primarily associated with polyarthritis and myalgia that can persist for months to years. On the other hand, New World alphaviruses such as VEEV cause mainly neurological disease. Despite the worldwide (re-)emergence of these viruses, there are no antivirals or vaccines available for the treatment or prevention of infections with alphaviruses. It is therefore of utmost importance to develop antiviral strategies against these viruses. We here provided an overview of the reported antiviral strategies against arthritogenic alphaviruses. In addition, we highlighted the future perspectives for the development and the proper use of such antivirals.
Keywords	arbovirus ; alphavirus ; chikungunya ; antivirals ; capping ; protease ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Repurposing Drugs for Mayaro Virus

Lana Langendries / Rana Abdelnabi / Johan Neyts / Leen Delang

Microorganisms, Vol 9, Iss 734, p

Identification of EIDD-1931, Favipiravir and Suramin as Mayaro Virus Inhibitors

2021 Volume 734

Abstract: Despite the emerging threat of the Mayaro virus (MAYV) in Central and South-America, there are no licensed antivirals or vaccines available for this neglected mosquito-borne virus. Here, we optimized a robust antiviral assay based on the inhibition of ... ...

Abstract	Despite the emerging threat of the Mayaro virus (MAYV) in Central and South-America, there are no licensed antivirals or vaccines available for this neglected mosquito-borne virus. Here, we optimized a robust antiviral assay based on the inhibition of the cytopathogenic effect that could be used for high-throughput screening to identify MAYV inhibitors. We first evaluated different cell lines and virus inputs to determine the best conditions for a reliable and reproducible antiviral assay. Next, we used this assay to evaluate a panel of antiviral compounds with known activity against other arboviruses. Only three drugs were identified as inhibitors of MAYV: β-D-N 4 -hydroxycytidine (EIDD-1931), favipiravir and suramin. The in vitro anti-MAYV activity of these antiviral compounds was further confirmed in a virus yield assay. These antivirals can therefore serve as reference compounds for future anti-MAYV compound testing. In addition, it is of interest to further explore the activity of EIDD-1931 and its orally bioavailable pro-drug molnupiravir in animal infection models to determine whether it offers promise for the treatment of MAYV infection.
Keywords	Mayaro virus ; antivirals ; alphaviruses ; emerging viruses ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Favipiravir Does Not Inhibit Chikungunya Virus Replication in Mosquito Cells and Aedes aegypti Mosquitoes

Sofie Jacobs / Lanjiao Wang / Ana Lucia Rosales Rosas / Ria Van Berwaer / Evelien Vanderlinden / Anna-Bella Failloux / Lieve Naesens / Leen Delang

Microorganisms, Vol 9, Iss 944, p

2021 Volume 944

Abstract: Favipiravir (T-705) is a broad-spectrum antiviral drug that inhibits RNA viruses after intracellular conversion into its active form, T-705 ribofuranosyl 5′-triphosphate. We previously showed that T-705 is able to significantly inhibit the replication of ...

Abstract	Favipiravir (T-705) is a broad-spectrum antiviral drug that inhibits RNA viruses after intracellular conversion into its active form, T-705 ribofuranosyl 5′-triphosphate. We previously showed that T-705 is able to significantly inhibit the replication of chikungunya virus (CHIKV), an arbovirus transmitted by Aedes mosquitoes, in mammalian cells and in mouse models. In contrast, the effect of T-705 on CHIKV infection and replication in the mosquito vector is unknown. Since the antiviral activity of T-705 has been shown to be cell line-dependent, we studied here its antiviral efficacy in Aedes -derived mosquito cells and in Aedes aegypti mosquitoes. Interestingly, T-705 was devoid of anti-CHIKV activity in mosquito cells, despite being effective against CHIKV in Vero cells. By investigating the metabolic activation profile, we showed that, unlike Vero cells, mosquito cells were not able to convert T-705 into its active form. To explore whether alternative metabolization pathways might exist in vivo, Aedes aegypti mosquitoes were infected with CHIKV and administered T-705 via an artificial blood meal. Virus titrations of whole mosquitoes showed that T-705 was not able to reduce CHIKV infection in mosquitoes. Combined, these in vitro and in vivo data indicate that T-705 lacks antiviral activity in mosquitoes due to inadequate metabolic activation in this animal species.
Keywords	favipiravir ; T-705 ; activation ; antiviral activity ; mosquitoes ; chikungunya virus ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Viral Polymerase Inhibitor Reduces Zika Virus Replication in the Reproductive Organs of Male Mice

Sofie Jacobs / Leen Delang / Eric Verbeken / Johan Neyts / Suzanne J.F. Kaptein

International Journal of Molecular Sciences, Vol 20, Iss 9, p

2019 Volume 2122

Abstract: In humans, Zika virus and viral RNA have been detected in semen up to 2.2 months and 6 months post infection (pi), respectively. Although the contribution of sexual transmission to the spread of ZIKV is too low to sustain an outbreak, it can increase the ...

Abstract	In humans, Zika virus and viral RNA have been detected in semen up to 2.2 months and 6 months post infection (pi), respectively. Although the contribution of sexual transmission to the spread of ZIKV is too low to sustain an outbreak, it can increase the risk of infection and the epidemic size as well as prolong the duration of an outbreak. In this study, we explored the potential of antivirals to serve as an effective strategy to prevent sexual transmission. Male AG129 mice infected with a ZIKV isolate from Suriname were treated with the nucleoside analog, 7-deaza-2′- C -methyladenosine (7DMA), that was previously shown to be efficacious in reducing ZIKV viremia and delaying ZIKV-induced disease in mice. Following treatment, viral RNA and infectious virus titers were consistently reduced in the male reproductive organs compared to vehicle-treated mice. This reduction of ZIKV loads in the testis was confirmed by the detection of lower levels of ZIKV antigens. Our data illustrate the value of this mouse model to validate the efficacy of new potential ZIKV drugs at the level of the male reproductive system.
Keywords	antivirals ; sexual transmission ; Zika virus ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	570
Language	English
Publishing date	2019-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Glutathione is a highly efficient thermostabilizer of poliovirus Sabin strains

Abdelnabi, Rana / Johan Neyts / Leen Delang

Vaccine. 2017 Mar. 07, v. 35, no. 10

2017

Abstract: Glutathione (GSH) is the most abundant thiol peptide in animal cells and has a critical role in antioxidation. GSH was reported to be essential for stabilization of some enteroviruses, including poliovirus (PV), during viral morphogenesis. Here, we ... ...

Abstract	Glutathione (GSH) is the most abundant thiol peptide in animal cells and has a critical role in antioxidation. GSH was reported to be essential for stabilization of some enteroviruses, including poliovirus (PV), during viral morphogenesis. Here, we explored the potential use of GSH as a thermostabilizer of oral poliomyelitis vaccine (OPV) formulations. GSH significantly protected the three types of PV from heat-inactivation in a concentration-dependent manner. At a GSH concentration of 20mM, nearly complete protection was observed against heating temperatures up to 53°C for 2min.GSH also markedly protected PV1 from heat-inactivation and this up to 6 h at temperatures of 44°C and 46°C and 3 h at 48°C. The fact that GSH is naturally present at high concentration in the human body makes it an efficient candidate stabilizer for OPV formulations.
Keywords	Enterovirus ; glutathione ; heat inactivation ; humans ; morphogenesis ; temperature ; thiols ; vaccines
Language	English
Dates of publication	2017-0307
Size	p. 1370-1372.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2017.01.070
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Comparing infectivity and virulence of emerging SARS-CoV-2 variants in Syrian hamsters

Rana Abdelnabi / Robbert Boudewijns / Caroline S. Foo / Laura Seldeslachts / Lorena Sanchez-Felipe / Xin Zhang / Leen Delang / Piet Maes / Suzanne J.F. Kaptein / Birgit Weynand / Greetje Vande Velde / Johan Neyts / Kai Dallmeier

EBioMedicine, Vol 68, Iss , Pp 103403- (2021)

2021

Abstract: Background: Within one year after its emergence, more than 108 million people acquired SARS-CoV-2 and almost 2·4 million succumbed to COVID-19. New SARS-CoV-2 variants of concern (VoC) are emerging all over the world, with the threat of being more ... ...

Abstract	Background: Within one year after its emergence, more than 108 million people acquired SARS-CoV-2 and almost 2·4 million succumbed to COVID-19. New SARS-CoV-2 variants of concern (VoC) are emerging all over the world, with the threat of being more readily transmitted, being more virulent, or escaping naturally acquired and vaccine-induced immunity. At least three major prototypic VoC have been identified, i.e. the United Kingdom, UK (B.1.1.7), South African (B.1.351) and Brazilian (B.1.1.28.1) variants. These are replacing formerly dominant strains and sparking new COVID-19 epidemics. Methods: We studied the effect of infection with prototypic VoC from both B.1.1.7 and B.1.351 variants in female Syrian golden hamsters to assess their relative infectivity and virulence in direct comparison to two basal SARS-CoV-2 strains isolated in early 2020. Findings: A very efficient infection of the lower respiratory tract of hamsters by these VoC is observed. In line with clinical evidence from patients infected with these VoC, no major differences in disease outcome were observed as compared to the original strains as was quantified by (i) histological scoring, (ii) micro-computed tomography, and (iii) analysis of the expression profiles of selected antiviral and pro-inflammatory cytokine genes. Noteworthy however, in hamsters infected with VoC B.1.1.7, a particularly strong elevation of proinflammatory cytokines was detected. Interpretation: We established relevant preclinical infection models that will be pivotal to assess the efficacy of current and future vaccine(s) (candidates) as well as therapeutics (small molecules and antibodies) against two important SARS-CoV-2 VoC. Funding: Stated in the acknowledgment.
Keywords	Emergence ; Hamster model ; SARS-CoV-2 ; Variants of concern (VoC) ; Medicine ; R ; Medicine (General) ; R5-920
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Stable distinct core eukaryotic viromes in different mosquito species from Guadeloupe, using single mosquito viral metagenomics

Chenyan Shi / Leen Beller / Ward Deboutte / Kwe Claude Yinda / Leen Delang / Anubis Vega-Rúa / Anna-Bella Failloux / Jelle Matthijnssens

Microbiome, Vol 7, Iss 1, Pp 1-

2019 Volume 20

Abstract: Abstract Background Mosquitoes are the most important invertebrate viral vectors in humans and harbor a high diversity of understudied viruses, which has been shown in many mosquito virome studies in recent years. These studies generally performed ... ...

Abstract	Abstract Background Mosquitoes are the most important invertebrate viral vectors in humans and harbor a high diversity of understudied viruses, which has been shown in many mosquito virome studies in recent years. These studies generally performed metagenomics sequencing on pools of mosquitoes, without assessment of the viral diversity in individual mosquitoes. To address this issue, we applied our optimized viral metagenomics protocol (NetoVIR) to compare the virome of single and pooled Aedes aegypti and Culex quinquefasciatus mosquitoes collected from different locations in Guadeloupe, in 2016 and 2017. Results The total read number and viral reads proportion of samples containing a single mosquito have no significant difference compared with those of pools containing five mosquitoes, which proved the feasibility of using single mosquito for viral metagenomics. A comparative analysis of the virome revealed a higher abundance and more diverse eukaryotic virome in Aedes aegypti, whereas Culex quinquefasciatus harbors a richer and more diverse phageome. The majority of the identified eukaryotic viruses were mosquito-species specific. We further characterized the genomes of 11 novel eukaryotic viruses. Furthermore, qRT-PCR analyses of the six most abundant eukaryotic viruses indicated that the majority of individual mosquitoes were infected by several of the selected viruses with viral genome copies per mosquito ranging from 267 to 1.01 × 108 (median 7.5 × 106) for Ae. aegypti and 192 to 8.69 × 106 (median 4.87 × 104) for Cx. quinquefasciatus. Additionally, in Cx. quinquefasciatus, a number of phage contigs co-occurred with several marker genes of Wolbachia sp. strain wPip. Conclusions We firstly demonstrate the feasibility to use single mosquito for viral metagenomics, which can provide much more precise virome profiles of mosquito populations. Interspecific comparisons show striking differences in abundance and diversity between the viromes of Ae. aegypti and Cx. quinquefasciatus. Those two mosquito species seem ...
Keywords	Viral metagenomics ; Single mosquito ; Eukaryotic virome ; Phageome ; Core virome ; Guadeloupe ; Microbial ecology ; QR100-130
Subject code	572
Language	English
Publishing date	2019-08-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Antiviral Therapy for Hepatitis C Virus

Leen Delang / Lotte Coelmont / Johan Neyts

Viruses, Vol 2, Iss 4, Pp 826-

Beyond the Standard of Care

2010 Volume 866

Abstract: Hepatitis C virus (HCV) represents a major health burden, with an estimated 180 million chronically infected individuals worldwide. These patients are at increased risk of developing liver cirrhosis and hepatocellular carcinoma. Infection with HCV is the ...

Abstract	Hepatitis C virus (HCV) represents a major health burden, with an estimated 180 million chronically infected individuals worldwide. These patients are at increased risk of developing liver cirrhosis and hepatocellular carcinoma. Infection with HCV is the leading cause of liver transplantation in the Western world. Currently, the standard of care (SoC) consists of pegylated interferon alpha (pegIFN-α) and ribavirin (RBV). However this therapy has a limited efficacy and is associated with serious side effects. Therefore more tolerable, highly potent inhibitors of HCV replication are urgently needed. Both Specifically Targeted Antiviral Therapy for HCV (STAT-C) and inhibitors that are believed to interfere with the host-viral interaction are discussed.
Keywords	HCV ; new antivirals ; review ; Microbiology ; QR1-502 ; Science ; Q ; DOAJ:Microbiology ; DOAJ:Biology ; DOAJ:Biology and Life Sciences
Language	English
Publishing date	2010-03-01T00:00:00Z
Publisher	Molecular Diversity Preservation International
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Viral engagement with host receptors blocked by a novel class of tryptophan dendrimers that targets the 5-fold-axis of the enterovirus-A71 capsid.

Liang Sun / Hyunwook Lee / Hendrik Jan Thibaut / Kristina Lanko / Eva Rivero-Buceta / Carol Bator / Belen Martinez-Gualda / Kai Dallmeier / Leen Delang / Pieter Leyssen / Federico Gago / Ana San-Félix / Susan Hafenstein / Carmen Mirabelli / Johan Neyts

PLoS Pathogens, Vol 15, Iss 5, p e

2019 Volume 1007760

Abstract: Enterovirus A71 (EV-A71) is a non-polio neurotropic enterovirus with pandemic potential. There are no antiviral agents approved to prevent or treat EV-A71 infections. We here report on the molecular mechanism by which a novel class of tryptophan ... ...

Abstract	Enterovirus A71 (EV-A71) is a non-polio neurotropic enterovirus with pandemic potential. There are no antiviral agents approved to prevent or treat EV-A71 infections. We here report on the molecular mechanism by which a novel class of tryptophan dendrimers inhibits (at low nanomolar to high picomolar concentration) EV-A71 replication in vitro. A lead compound in the series (MADAL385) prevents binding and internalization of the virus but does not, unlike classical capsid binders, stabilize the particle. By means of resistance selection, reverse genetics and cryo-EM, we map the binding region of MADAL385 to the 5-fold vertex of the viral capsid and demonstrate that a single molecule binds to each vertex. By interacting with this region, MADAL385 prevents the interaction of the virus with its cellular receptors PSGL1 and heparan sulfate, thereby blocking the attachment of EV-A71 to the host cells.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2019-05-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A novel druggable interprotomer pocket in the capsid of rhino- and enteroviruses.

Rana Abdelnabi / James A Geraets / Yipeng Ma / Carmen Mirabelli / Justin W Flatt / Aušra Domanska / Leen Delang / Dirk Jochmans / Timiri Ajay Kumar / Venkatesan Jayaprakash / Barij Nayan Sinha / Pieter Leyssen / Sarah J Butcher / Johan Neyts

PLoS Biology, Vol 17, Iss 6, p e

2019 Volume 3000281

Abstract: Rhino- and enteroviruses are important human pathogens, against which no antivirals are available. The best-studied inhibitors are "capsid binders" that fit in a hydrophobic pocket of the viral capsid. Employing a new class of entero-/rhinovirus ... ...

Abstract	Rhino- and enteroviruses are important human pathogens, against which no antivirals are available. The best-studied inhibitors are "capsid binders" that fit in a hydrophobic pocket of the viral capsid. Employing a new class of entero-/rhinovirus inhibitors and by means of cryo-electron microscopy (EM), followed by resistance selection and reverse genetics, we discovered a hitherto unknown druggable pocket that is formed by viral proteins VP1 and VP3 and that is conserved across entero-/rhinovirus species. We propose that these inhibitors stabilize a key region of the virion, thereby preventing the conformational expansion needed for viral RNA release. A medicinal chemistry effort resulted in the identification of analogues targeting this pocket with broad-spectrum activity against Coxsackieviruses B (CVBs) and compounds with activity against enteroviruses (EV) of groups C and D, and even rhinoviruses (RV). Our findings provide novel insights in the biology of the entry of entero-/rhinoviruses and open new avenues for the design of broad-spectrum antivirals against these pathogens.
Keywords	Biology (General) ; QH301-705.5
Subject code	540
Language	English
Publishing date	2019-06-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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