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  1. 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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  2. 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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  3. Article ; Online: Nirmatrelvir-resistant SARS-CoV-2 is efficiently transmitted in female Syrian hamsters and retains partial susceptibility to treatment

    Rana Abdelnabi / Dirk Jochmans / Kim Donckers / Bettina Trüeb / Nadine Ebert / Birgit Weynand / Volker Thiel / Johan Neyts

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 7

    Abstract: Abstract The SARS-CoV-2 main protease (3CLpro) is one of the promising therapeutic targets for the treatment of COVID-19. Nirmatrelvir is the first 3CLpro inhibitor authorized for treatment of COVID-19 patients at high risk of hospitalization. We ... ...

    Abstract Abstract The SARS-CoV-2 main protease (3CLpro) is one of the promising therapeutic targets for the treatment of COVID-19. Nirmatrelvir is the first 3CLpro inhibitor authorized for treatment of COVID-19 patients at high risk of hospitalization. We recently reported on the in vitro selection of SARS-CoV-2 3CLpro resistant virus (L50F-E166A-L167F; 3CLprores) that is cross-resistant with nirmatrelvir and other 3CLpro inhibitors. Here, we demonstrate that the 3CLprores virus replicates efficiently in the lungs of intranasally infected female Syrian hamsters and causes lung pathology comparable to that caused by the WT virus. Moreover, hamsters infected with 3CLprores virus transmit the virus efficiently to co-housed non-infected contact hamsters. Importantly, at a dose of 200 mg/kg (BID) of nirmatrelvir, the compound was still able to reduce the lung infectious virus titers of 3CLprores-infected hamsters by 1.4 log10 with a modest improvement in the lung histopathology as compared to the vehicle control. Fortunately, resistance to Nirmatrelvir does not readily develop in clinical setting. Yet, as we demonstrate, in case drug-resistant viruses emerge, they may spread easily which may thus impact therapeutic options. Therefore, the use of 3CLpro inhibitors in combination with other drugs may be considered, especially in immunodeficient patients, to avoid the development of drug-resistant viruses.
    Keywords Science ; Q
    Subject code 616
    Language English
    Publishing date 2023-04-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Ivermectin Does Not Protect against SARS-CoV-2 Infection in the Syrian Hamster Model

    Caroline S. Foo / Rana Abdelnabi / Laura Vangeel / Steven De Jonghe / Dirk Jochmans / Birgit Weynand / Johan Neyts

    Microorganisms, Vol 10, Iss 633, p

    2022  Volume 633

    Abstract: Ivermectin, an FDA-approved antiparasitic drug, has been reported to have in vitro activity against SARS-CoV-2. Increased off-label use of ivermectin for COVID-19 has been reported. We here assessed the effect of ivermectin in Syrian hamsters infected ... ...

    Abstract Ivermectin, an FDA-approved antiparasitic drug, has been reported to have in vitro activity against SARS-CoV-2. Increased off-label use of ivermectin for COVID-19 has been reported. We here assessed the effect of ivermectin in Syrian hamsters infected with the SARS-CoV-2 Beta (B.1.351) variant. Infected animals received a clinically relevant dose of ivermectin (0.4 mg/kg subcutaneously dosed) once daily for four consecutive days after which the effect was quantified. Ivermectin monotherapy did not reduce lung viral load and even significantly worsened SARS-CoV-2-induced lung pathology. Additionally, it did not potentiate the activity of molnupiravir (Lagevrio TM ) when combined with this drug. This study contributes to the growing body of evidence that ivermectin does not result in a beneficial effect in the treatment of COVID-19. These findings are important given the increasing, dangerous off-label use of ivermectin for the treatment of COVID-19.
    Keywords COVID-19 ; ivermectin ; molnupiravir ; off-label use ; hamster model ; Biology (General) ; QH301-705.5
    Subject code 630
    Language English
    Publishing date 2022-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Integrating artificial intelligence-based epitope prediction in a SARS-CoV-2 antibody discovery pipeline

    Delphine Diana Acar / Wojciech Witkowski / Magdalena Wejda / Ruifang Wei / Tim Desmet / Bert Schepens / Sieglinde De Cae / Koen Sedeyn / Hannah Eeckhaut / Daria Fijalkowska / Kenny Roose / Sandrine Vanmarcke / Anne Poupon / Dirk Jochmans / Xin Zhang / Rana Abdelnabi / Caroline S. Foo / Birgit Weynand / Dirk Reiter /
    Nico Callewaert / Han Remaut / Johan Neyts / Xavier Saelens / Sarah Gerlo / Linos Vandekerckhove

    EBioMedicine, Vol 100, Iss , Pp 104960- (2024)

    caution is warrantedResearch in context

    2024  

    Abstract: Summary: Background: SARS-CoV-2-neutralizing antibodies (nABs) showed great promise in the early phases of the COVID-19 pandemic. The emergence of resistant strains, however, quickly rendered the majority of clinically approved nABs ineffective. This ... ...

    Abstract Summary: Background: SARS-CoV-2-neutralizing antibodies (nABs) showed great promise in the early phases of the COVID-19 pandemic. The emergence of resistant strains, however, quickly rendered the majority of clinically approved nABs ineffective. This underscored the imperative to develop nAB cocktails targeting non-overlapping epitopes. Methods: Undertaking a nAB discovery program, we employed a classical workflow, while integrating artificial intelligence (AI)-based prediction to select non-competing nABs very early in the pipeline. We identified and in vivo validated (in female Syrian hamsters) two highly potent nABs. Findings: Despite the promising results, in depth cryo-EM structural analysis demonstrated that the AI-based prediction employed with the intention to ensure non-overlapping epitopes was inaccurate. The two nABs in fact bound to the same receptor-binding epitope in a remarkably similar manner. Interpretation: Our findings indicate that, even in the Alphafold era, AI-based predictions of paratope-epitope interactions are rough and experimental validation of epitopes remains an essential cornerstone of a successful nAB lead selection. Funding: Full list of funders is provided at the end of the manuscript.
    Keywords SARS-CoV-2 ; Neutralizing antibody ; In silico prediction ; Epitope mapping ; Covid-19 ; Medicine ; R ; Medicine (General) ; R5-920
    Subject code 570
    Language English
    Publishing date 2024-02-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Updated vaccine protects against SARS-CoV-2 variants including Omicron (B.1.1.529) and prevents transmission in hamsters

    Sapna Sharma / Thomas Vercruysse / Lorena Sanchez-Felipe / Winnie Kerstens / Madina Rasulova / Lindsey Bervoets / Carolien De Keyzer / Rana Abdelnabi / Caroline S. Foo / Viktor Lemmens / Dominique Van Looveren / Piet Maes / Guy Baele / Birgit Weynand / Philippe Lemey / Johan Neyts / Hendrik Jan Thibaut / Kai Dallmeier

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 11

    Abstract: Currently licensed COVID-19 vaccines are based on antigen sequences of early SARS-CoV-2 isolates, despite the prevalence of variants of concerns escaping vaccine-mediated protection. Using their updated yellow fever 17D vectored candidate, here, authors ... ...

    Abstract Currently licensed COVID-19 vaccines are based on antigen sequences of early SARS-CoV-2 isolates, despite the prevalence of variants of concerns escaping vaccine-mediated protection. Using their updated yellow fever 17D vectored candidate, here, authors assess neutralising antibody responses against variants of concern, and demonstrate protection and reduced transmission in a hamster model.
    Keywords Science ; Q
    Language English
    Publishing date 2022-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. 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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  8. Article ; Online: The oral protease inhibitor (PF-07321332) protects Syrian hamsters against infection with SARS-CoV-2 variants of concern

    Rana Abdelnabi / Caroline S. Foo / Dirk Jochmans / Laura Vangeel / Steven De Jonghe / Patrick Augustijns / Raf Mols / Birgit Weynand / Thanaporn Wattanakul / Richard M. Hoglund / Joel Tarning / Charles E. Mowbray / Peter Sjö / Fanny Escudié / Ivan Scandale / Eric Chatelain / Johan Neyts

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 9

    Abstract: There is an urgent need for anti-virals targeting SARS-CoV-2. One of the most promising viral targets is the main protease of SARS-CoV-2, which is essential for viral replication and has no human analogue. Here, Abdelnabi et al. show that one of the most ...

    Abstract There is an urgent need for anti-virals targeting SARS-CoV-2. One of the most promising viral targets is the main protease of SARS-CoV-2, which is essential for viral replication and has no human analogue. Here, Abdelnabi et al. show that one of the most promising anti-virals (PF-07321332), currently in clinical trials, protects against SARS-CoV-2 alpha, beta and delta variant infection and provide evidence of reduced transmission.
    Keywords Science ; Q
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. 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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