RNA Viruses: Replication, Assembly and Antivirals

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (1 April 2023) | Viewed by 17899

Special Issue Editor

Institute of Biophysics (IBF-CNR), National Research Council, Genova, Italy
Interests: structural biology; antivirals; apoptosis; computational modelling; drug discovery

Special Issue Information

Dear Colleagues,

The number of fatalities that occur worldwide as the result of viral infections counts millions of individuals annually. Almost all newly emerging human pathogenic viruses belong to the group of RNA viruses. An emblematic example is provided by the viruses Ebola and Zika which have re-emerged and by the recent SARS-CoV-2. Expert opinion predicts that novel and potentially highly lethal RNA viruses will continue to emerge from the large, genetically variable natural pools surrounding us. Thus, there is an urgent need to be prepared to face such threats. The identification and characterization of molecular determinants involved in the replication and assembly of RNA viruses might pave the way for rational discovery of antiviral therapeutics.

In this Special Issue, we welcome full-length original articles and review papers on both fundamental and applied aspects of RNA virus biology, structural virology, and novel computational or experimental strategies for determining the structures of RNA viruses and of viral proteins involved in replication, for the identification of new antiviral molecules or repurposing of drugs as antivirals, and for preclinical studies of antivirals previously identified.

Dr. Eloise Mastrangelo
Guest Editor

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Keywords

  • antivirals
  • structural virology
  • mechanism of infection
  • computational methods

Published Papers (10 papers)

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Research

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19 pages, 10934 KiB  
Article
Significant Broad-Spectrum Antiviral Activity of Bi121 against Different Variants of SARS-CoV-2
by Bobban Subhadra, Ragini Agrawal, Virender Kumar Pal, Agnes-Laurence Chenine, Jeffy George Mattathil and Amit Singh
Viruses 2023, 15(6), 1299; https://doi.org/10.3390/v15061299 - 31 May 2023
Cited by 3 | Viewed by 2431
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has so far infected 762 million people with over 6.9 million deaths worldwide. Broad-spectrum viral inhibitors that block the initial stages of infection by reducing virus binding and proliferation, thereby reducing disease severities, are still an [...] Read more.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has so far infected 762 million people with over 6.9 million deaths worldwide. Broad-spectrum viral inhibitors that block the initial stages of infection by reducing virus binding and proliferation, thereby reducing disease severities, are still an unmet global medical need. We studied Bi121, which is a standardized polyphenolic-rich compound isolated from Pelargonium sidoides, against recombinant vesicular stomatitis virus (rVSV)-pseudotyped SARS-CoV-2S (mutations in the spike protein) of six different variants of SARS-CoV-2. Bi121 was effective at neutralizing all six rVSV-ΔG-SARS-CoV-2S variants. The antiviral activity of Bi121 was also assessed against SARS-CoV-2 variants (USA WA1/2020, Hongkong/VM20001061/2020, B.1.167.2 (Delta), and Omicron) in Vero cells and HEK-ACE2 cell lines using RT-qPCR and plaque assays. Bi121 showed significant antiviral activity against all the four SARS-CoV-2 variants tested, suggesting a broad-spectrum activity. Bi121 fractions generated using HPLC showed antiviral activity in three fractions out of eight against SARS-CoV-2. The dominant compound identified in all three fractions using LC/MS/MS analysis was Neoilludin B. In silico structural modeling studies with Neoilludin B showed that it has a novel RNA-intercalating activity toward RNA viruses. In silico findings and the antiviral activity of this compound against several SARS-CoV-2 variants support further evaluation as a potential treatment of COVID-19. Full article
(This article belongs to the Special Issue RNA Viruses: Replication, Assembly and Antivirals)
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20 pages, 7436 KiB  
Article
Infectious Bursal Disease Virus Assembly Causes Endoplasmic Reticulum Stress and Lipid Droplet Accumulation
by Yesica R. Frontini-López, Lautaro Rivera, Cristian A. Pocognoni, Julieta S. Roldán, María I. Colombo, Marina Uhart and Laura R. Delgui
Viruses 2023, 15(6), 1295; https://doi.org/10.3390/v15061295 - 31 May 2023
Viewed by 1450
Abstract
Gumboro illness is caused by the highly contagious immunosuppressive infectious bursal disease virus (IBDV), which affects the poultry industry globally. We have previously shown that IBDV hijacks the endocytic pathway to construct viral replication complexes on endosomes linked to the Golgi complex (GC). [...] Read more.
Gumboro illness is caused by the highly contagious immunosuppressive infectious bursal disease virus (IBDV), which affects the poultry industry globally. We have previously shown that IBDV hijacks the endocytic pathway to construct viral replication complexes on endosomes linked to the Golgi complex (GC). Then, analyzing crucial proteins involved in the secretory pathway, we showed the essential requirement of Rab1b, the Rab1b downstream effector Golgi-specific BFA resistance factor 1 (GBF1), and its substrate, the small GTPase ADP-ribosylation factor 1 (ARF1), for IBDV replication. In the current work, we focused on elucidating the IBDV assembly sites. We show that viral assembly occurs within single-membrane compartments closely associated with endoplasmic reticulum (ER) membranes, though we failed to elucidate the exact nature of the virus-wrapping membranes. Additionally, we show that IBDV infection promotes the stress of the ER, characterized by an accumulation of the chaperone binding protein (BiP) and lipid droplets (LDs) in the host cells. Overall, our results represent further original data showing the interplay between IBDV and the secretory pathway, making a substantial contribution to the field of birnaviruses–host cell interactions. Full article
(This article belongs to the Special Issue RNA Viruses: Replication, Assembly and Antivirals)
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21 pages, 8120 KiB  
Article
Structural Investigations on Novel Non-Nucleoside Inhibitors of Human Norovirus Polymerase
by Gilda Giancotti, Giulio Nannetti, Gilda Padalino, Martina Landini, Nanci Santos-Ferreira, Jana Van Dycke, Valentina Naccarato, Usheer Patel, Romano Silvestri, Johan Neyts, Roberto Gozalbo-Rovira, Jésus Rodríguez-Díaz, Joana Rocha-Pereira, Andrea Brancale, Salvatore Ferla and Marcella Bassetto
Viruses 2023, 15(1), 74; https://doi.org/10.3390/v15010074 - 27 Dec 2022
Viewed by 2609
Abstract
Human norovirus is the first cause of foodborne disease worldwide, leading to extensive outbreaks of acute gastroenteritis, and causing around 200,000 children to die annually in developing countries. No specific vaccines or antiviral agents are currently available, with therapeutic options limited to supportive [...] Read more.
Human norovirus is the first cause of foodborne disease worldwide, leading to extensive outbreaks of acute gastroenteritis, and causing around 200,000 children to die annually in developing countries. No specific vaccines or antiviral agents are currently available, with therapeutic options limited to supportive care to prevent dehydration. The infection can become severe and lead to life-threatening complications in young children, the elderly and immunocompromised individuals, leading to a clear need for antiviral agents, to be used as treatments and as prophylactic measures in case of outbreaks. Due to the key role played by the viral RNA-dependent RNA polymerase (RdRp) in the virus life cycle, this enzyme is a promising target for antiviral drug discovery. In previous studies, following in silico investigations, we identified different small-molecule inhibitors of this enzyme. In this study, we rationally modified five identified scaffolds, to further explore structure–activity relationships, and to enhance binding to the RdRp. The newly designed compounds were synthesized according to multiple-step synthetic routes and evaluated for their inhibition of the enzyme in vitro. New inhibitors with low micromolar inhibitory activity of the RdRp were identified, which provide a promising basis for further hit-to-lead optimization. Full article
(This article belongs to the Special Issue RNA Viruses: Replication, Assembly and Antivirals)
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14 pages, 2662 KiB  
Article
In Vitro Evaluation of Anti-Rotaviral Activity and Intestinal Toxicity of a Phytotherapeutic Prototype of Achyrocline bogotensis (Kunth) DC.
by María-Camila Ramírez, Kelly Méndez, Alicia Castelblanco-Mora, Sandra Quijano and Juan Ulloa
Viruses 2022, 14(11), 2394; https://doi.org/10.3390/v14112394 - 29 Oct 2022
Cited by 1 | Viewed by 1233
Abstract
Viruses represent the primary etiologic agents (70–80%) of acute diarrheal disease (ADD), and rotavirus (RV) is the most relevant one. Currently, four rotavirus vaccines are available. However, these vaccines do not protect against emerging viral strains or are not available in low-income countries. [...] Read more.
Viruses represent the primary etiologic agents (70–80%) of acute diarrheal disease (ADD), and rotavirus (RV) is the most relevant one. Currently, four rotavirus vaccines are available. However, these vaccines do not protect against emerging viral strains or are not available in low-income countries. To date, there are no approved drugs available against rotavirus infection. In this study, we evaluated the in vitro anti-rotaviral activity and intestinal toxicity of a phytotherapeutic prototype obtained from Achyrocline bogotensis (Kunth) DC. (PPAb); medicinal plant that contains compounds that inhibit the rotavirus replication cycle. Virucidal and viral yield reduction effects exerted by the PPAb were evaluated by immunocytochemistry and flow cytometry. Furthermore, the toxic impact of the PPAb was evaluated in polarized human intestinal epithelial C2BBe1 cells in terms of cytotoxicity, loss of cytoplasmic membrane asymmetry, and DNA fragmentation by MTT and fluorometry. PPAb concentrations under 0.49 mg/mL exerted significant virucidal and viral yield reduction activities, and concentrations under 16 mg/mL neither reduced cell viability, produced DNA fragmentation, nor compromised the C2BBe1cell membrane stability after 24-h incubation. Based on these results, the evaluated phytotherapeutic prototype of Achyrocline bogotensis might be considered as a promising alternative to treat ADD caused by rotavirus. Full article
(This article belongs to the Special Issue RNA Viruses: Replication, Assembly and Antivirals)
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17 pages, 4349 KiB  
Article
Quercetin Inhibits Hsp70 Blocking of Bovine Viral Diarrhea Virus Infection and Replication in the Early Stage of Virus Infection
by Nannan Chen, Yu Liu, Tongtong Bai, Jinwei Chen, Zhibo Zhao, Jing Li, Baihui Shao, Zecai Zhang, Yulong Zhou, Xue Wang and Zhanbo Zhu
Viruses 2022, 14(11), 2365; https://doi.org/10.3390/v14112365 - 26 Oct 2022
Cited by 6 | Viewed by 1779
Abstract
Bovine viral diarrhea virus (BVDV), a positive-strand RNA virus of the genus Pestivirus in the Flaviviridae family, is the causative agent of viral diarrheal disease in bovine. BVDV has been used as a surrogate model for the hepatitis C virus (HCV) to evaluate [...] Read more.
Bovine viral diarrhea virus (BVDV), a positive-strand RNA virus of the genus Pestivirus in the Flaviviridae family, is the causative agent of viral diarrheal disease in bovine. BVDV has been used as a surrogate model for the hepatitis C virus (HCV) to evaluate the efficacy of antiviral drugs. The plant flavonol quercetin causes multiple health-promoting effects in humans and animals. It can be made into a variety of additives, and it exerts a variety of immunomodulatory effects with the potential to be used as an antiviral agent. However, quercetin’s antiviral effect and mechanism of action on BVDV are still unclear. Therefore, this study was designed to evaluate quercetin’s effect on BVDV virus replication in vitro and in vivo and elucidate its mechanism of action. A CCK-8 kit was used to analyze the toxicity of the quercetin to the MDBK cells. Western blot, qRT-PCR, TCID50, and histological analysis were used to determine the mechanism of quercetin’s anti-BVDV activity. An oxidative stress kit was used to evaluate the effects of quercetin on ROS, antioxidant enzymes, and MDA indexes. The effect of quercetin on IL-2 and IFN-γ in the serum of mice was determined by using an ELISA kit. The results showed that quercetin inhibits Hsp70, blocks BVDV infection in the early stage of virus infection and inhibits BVDV replication by inhibiting oxidative stress or ERK phosphorylation. In addition, quercetin alleviated the decrease in IFN-γ and IL-2 in the serum of BVDV-infected mice. Quercetin ameliorated BVDV-induced histopathological changes. In summary, this study demonstrated for the first time the role of Hsp70 in BVDV infection and the potential application of quercetin in treating BVDV infection. Full article
(This article belongs to the Special Issue RNA Viruses: Replication, Assembly and Antivirals)
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9 pages, 667 KiB  
Article
Efficacy of Licensed Monoclonal Antibodies and Antiviral Agents against the SARS-CoV-2 Omicron Sublineages BA.1 and BA.2
by Lia Fiaschi, Filippo Dragoni, Elisabetta Schiaroli, Annalisa Bergna, Barbara Rossetti, Federica Giammarino, Camilla Biba, Anna Gidari, Alessia Lai, Cesira Nencioni, Daniela Francisci, Maurizio Zazzi and Ilaria Vicenti
Viruses 2022, 14(7), 1374; https://doi.org/10.3390/v14071374 - 23 Jun 2022
Cited by 17 | Viewed by 2219
Abstract
Newly emerging SARS-CoV-2 variants may escape monoclonal antibodies (mAbs) and antiviral drugs. By using live virus assays, we assessed the ex vivo inhibition of the B.1 wild-type (WT), delta and omicron BA.1 and BA.2 lineages by post-infusion sera from 40 individuals treated with [...] Read more.
Newly emerging SARS-CoV-2 variants may escape monoclonal antibodies (mAbs) and antiviral drugs. By using live virus assays, we assessed the ex vivo inhibition of the B.1 wild-type (WT), delta and omicron BA.1 and BA.2 lineages by post-infusion sera from 40 individuals treated with bamlanivimab/etesevimab (BAM/ETE), casirivimab/imdevimab (CAS/IMD), and sotrovimab (SOT) as well as the activity of remdesivir, nirmatrelvir and molnupiravir. mAbs and drug activity were defined as the serum dilution (ID50) and drug concentration (IC50), respectively, showing 50% protection of virus-induced cytopathic effect. All pre-infusion sera were negative for SARS-CoV-2 neutralizing activity. BAM/ETE, CAS/IMD, and SOT showed activity against the WT (ID50 6295 (4355–8075) for BAM/ETE; 18,214 (16,248–21,365) for CAS/IMD; and 456 (265–592) for SOT) and the delta (14,780 (ID50 10,905–21,020) for BAM/ETE; 63,937 (47,211–79,971) for CAS/IMD; and 1103 (843–1334) for SOT). Notably, only SOT was active against BA.1 (ID50 200 (37–233)), whereas BA.2 was neutralized by CAS/IMD (ID50 174 (134–209) ID50) and SOT (ID50 20 (9–31) ID50), but not by BAM/ETE. No significant inter-variant IC50 differences were observed for molnupiravir (1.5 ± 0.1/1.5 ± 0.7/1.0 ± 0.5/0.8 ± 0.01 μM for WT/delta/BA.1/BA.2, respectively), nirmatrelvir (0.05 ± 0.02/0.06 ± 0.01/0.04 ± 0.02/0.04 ± 0.01 μM) or remdesivir (0.08 ± 0.04/0.11 ± 0.08/0.05 ± 0.04/0.08 ± 0.01 μM). Continued evolution of SARS-CoV-2 requires updating the mAbs arsenal, although antivirals have so far remained unaffected. Full article
(This article belongs to the Special Issue RNA Viruses: Replication, Assembly and Antivirals)
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14 pages, 1717 KiB  
Article
Virucidal Activity of the Pyridobenzothiazolone Derivative HeE1-17Y against Enveloped RNA Viruses
by Rafaela Milan Bonotto, Francesco Bonì, Mario Milani, Antonio Chaves-Sanjuan, Silvia Franze, Francesca Selmin, Tommaso Felicetti, Martino Bolognesi, Soultana Konstantinidou, Monica Poggianella, Chantal L. Márquez, Federica Dattola, Monica Zoppè, Giuseppe Manfroni, Eloise Mastrangelo and Alessandro Marcello
Viruses 2022, 14(6), 1157; https://doi.org/10.3390/v14061157 - 27 May 2022
Cited by 4 | Viewed by 1846
Abstract
Pyridobenzothiazolone derivatives are a promising class of broad-spectrum antivirals. However, the mode of action of these compounds remains poorly understood. The HeE1-17Y derivative has already been shown to be a potent compound against a variety of flaviviruses of global relevance. In this work, [...] Read more.
Pyridobenzothiazolone derivatives are a promising class of broad-spectrum antivirals. However, the mode of action of these compounds remains poorly understood. The HeE1-17Y derivative has already been shown to be a potent compound against a variety of flaviviruses of global relevance. In this work, the mode of action of HeE1-17Y has been studied for West Nile virus taking advantage of reporter replication particles (RRPs). Viral infectivity was drastically reduced by incubating the compound with the virus before infection, thus suggesting a direct interaction with the viral particles. Indeed, RRPs incubated with the inhibitor appeared to be severely compromised in electron microscopy analysis. HeE1-17Y is active against other enveloped viruses, including SARS-CoV-2, but not against two non-enveloped viruses, suggesting a virucidal mechanism that involves the alteration of the viral membrane. Full article
(This article belongs to the Special Issue RNA Viruses: Replication, Assembly and Antivirals)
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Review

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10 pages, 737 KiB  
Review
The Envelope (E) Protein of SARS-CoV-2 as a Pharmacological Target
by Teresa Santos-Mendoza
Viruses 2023, 15(4), 1000; https://doi.org/10.3390/v15041000 - 19 Apr 2023
Cited by 6 | Viewed by 2500
Abstract
The COVID-19 pandemic caused by the SARS-CoV-2 virus is still a global health concern. Several spike (S) protein-based vaccines have been developed that efficiently protect the human population against severe forms of COVID-19. However, some SARS-CoV-2 variants of concern (VOCs) have emerged that [...] Read more.
The COVID-19 pandemic caused by the SARS-CoV-2 virus is still a global health concern. Several spike (S) protein-based vaccines have been developed that efficiently protect the human population against severe forms of COVID-19. However, some SARS-CoV-2 variants of concern (VOCs) have emerged that evade the protective effect of vaccine-induced antibodies. Therefore, efficient and specific antiviral treatments to control COVID-19 are indispensable. To date, two drugs have been approved for mild COVID-19 treatment; nevertheless, more drugs, preferably broad-spectrum and ready-to-use therapeutic agents for new pandemics, are needed. Here, I discuss the PDZ-dependent protein-protein interactions of the viral E protein with host proteins as attractive alternatives for the development of antivirals against coronavirus. Full article
(This article belongs to the Special Issue RNA Viruses: Replication, Assembly and Antivirals)
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Other

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5 pages, 1534 KiB  
Reply
Reply to Kulić, Ž. Comment on “Subhadra et al. Significant Broad-Spectrum Antiviral Activity of Bi121 against Different Variants of SARS-CoV-2. Viruses 2023, 15, 1299”
by Bobban Subhadra, Ragini Agrawal, Virender Kumar Pal, Agnes-Laurence Chenine, Jeffy George Mattathil and Amit Singh
Viruses 2023, 15(11), 2269; https://doi.org/10.3390/v15112269 - 17 Nov 2023
Viewed by 481
Abstract
We would like to thank Dr. Žarko Kulić [...] Full article
(This article belongs to the Special Issue RNA Viruses: Replication, Assembly and Antivirals)
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3 pages, 177 KiB  
Comment
Comment on Subhadra et al. Significant Broad-Spectrum Antiviral Activity of Bi121 against Different Variants of SARS-CoV-2. Viruses 2023, 15, 1299
by Žarko Kulić
Viruses 2023, 15(11), 2268; https://doi.org/10.3390/v15112268 - 17 Nov 2023
Cited by 1 | Viewed by 494
Abstract
The article “Significant Broad-Spectrum Antiviral Activity of Bi121 against Different Variants of SARS-CoV-2” by Subhadra et al. [...] Full article
(This article belongs to the Special Issue RNA Viruses: Replication, Assembly and Antivirals)
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