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Recent Advances in Antivirals for Emerging Viruses 2.0

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A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Virology".

Deadline for manuscript submissions: closed (22 May 2023) | Viewed by 81082

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Special Issue Editors

Dr. Keivan Zandi

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Guest Editor

School of Medicine, Department of Pediatrics, Emory University, Atlanta, GA, USA
Interests: antiviral research; arbovirology; molecular virology; natural products for drug discovery; infectious disease; molecular epidemiology; cancer research
Special Issues, Collections and Topics in MDPI journals

Dr. James J. Kohler

E-Mail Website
Guest Editor

Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, USA
Interests: antiviral agents; broad-spectrum antivirals; antiviral response; emerging and re-emerging viral diseases; antiviral strategies; druggable antiviral targets; direct acting antivirals; host-directed antivirals; drug-resistant viruses
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous Special Issue "Recent Advances in Antivirals for Emerging Viruses", which was published in 2021. https://www.mdpi.com/journal/microorganisms/special_issues/Antivir_Emerg_Viruses

The emergence of COVID-19 is a reminder that new transmissible viruses have potential global social, health, and economic impacts. Recently developed biological tools (including rapid and efficient cloning and sequencing) have advanced scientific efforts to identify the viral enzymes of important novel and re-emerging human viruses (e.g., Dengue, West Nile, Zika, Chikungunya, influenza, and now coronaviruses). At the same time, drug discovery has expanded exponentially, resulting in vast libraries of compounds for screening direct antiviral activity. This Special Issue will highlight recent advances in antiviral drug developments, including:

1) directly acting antivirals;

2) modifiers of immune activation;

3) inhibitors of specific cell activation pathways.

Dr. Keivan Zandi
Dr. James J. Kohler
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Microorganisms is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

antiviral agents
broad-spectrum antivirals
antiviral response
emerging and re-emerging viral diseases
antiviral strategies
druggable antiviral targets
direct acting antivirals
host-directed antivirals
drug-resistant viruses

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Published Papers (10 papers)

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Research

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11 pages, 289 KiB

Open AccessArticle

Adenovirus Infection in Hematopoietic and Solid Organ Paediatric Transplant Recipients: Treatment, Outcomes, and Use of Cidofovir

by Carlos Grasa, Einés Monteagudo-Vilavedra, Elena Pérez-Arenas, Iker Falces-Romero, Yasmina Mozo del Castillo, Cristina Schüffelmann-Gutiérrez, Teresa del Rosal, Ana Méndez-Echevarría, Fernando Baquero-Artigao, Alejandro Zarauza Santoveña, Pilar Serrano Fernández, Talía Sainz and Cristina Calvo

Microorganisms 2023, 11(7), 1750; https://doi.org/10.3390/microorganisms11071750 - 4 Jul 2023

Cited by 2 | Viewed by 1760

Abstract

Background: human adenovirus (hAdV) infection constitutes an important cause of morbidity and mortality in transplant recipients, due to their immune status. Among drugs currently available, cidofovir (CDF) is the most prescribed. Methods: Retrospective study of hAdV infection in paediatric transplant recipients from a tertiary paediatric centre, describing characteristics, management, and outcomes, and focused on the role of CDF. Results: 49 episodes of infection by hAdV were detected during a four-year period: 38 episodes in patients that received allogeneic hematopoietic stem cell transplantation (77.6%) and 11 in solid organ transplant recipients (22.4%). Twenty-five patients (52.1%) were symptomatic, presenting mainly fever and/or diarrhoea. CDF was prescribed in 24 patients (49%), with modest results. CDF use was associated with the presence of symptoms resulting in lower lymphocyte count, paediatric intensive care unit admission, and high viral load. Other therapeutic measures included administration of intravenous immunoglobulin, reducing immunosuppression, and T-lymphocyte infusion. Despite treatment, 22.9% of patients did not resolve the infection and there were three deaths related to hAdV infection. All-cause mortality was 16.7% (8 episodes) by 30 days, and 32.7% (16 episodes) by 90 days, of which, 3 episodes (3/16, 18.8%) were attributed to hAdV directly. Conclusions: hAdV infection had high morbidity and mortality in our series. CDF use is controversial, and available therapeutic options are limited. Transplant patients with low lymphocyte count are at higher risk of persistent positive viremias, and short-term survival of these patients was influenced by the resolution of hAdV infection. Full article

(This article belongs to the Special Issue Recent Advances in Antivirals for Emerging Viruses 2.0)

15 pages, 812 KiB

Open AccessArticle

Favipiravir Suppresses Zika Virus (ZIKV) through Activity as a Mutagen

by Evelyn J. Franco, Eleonora Cella, Xun Tao, Kaley C. Hanrahan, Taj Azarian and Ashley N. Brown

Microorganisms 2023, 11(5), 1342; https://doi.org/10.3390/microorganisms11051342 - 19 May 2023

Cited by 4 | Viewed by 1506

Abstract

In a companion paper, we demonstrated that the nucleoside analogue favipiravir (FAV) suppressed Zika virus (ZIKV) replication in three human-derived cell lines—HeLa, SK-N-MC, and HUH-7. Our results revealed that FAV’s effect was most pronounced in HeLa cells. In this work, we aimed to explain variation in FAV activity, investigating its mechanism of action and characterizing host cell factors relevant to tissue-specific differences in drug effect. Using viral genome sequencing, we show that FAV therapy was associated with an increase in the number of mutations and promoted the production of defective viral particles in all three cell lines. Our findings demonstrate that defective viral particles made up a larger portion of the viral population released from HeLa cells both at increasing FAV concentrations and at increasing exposure times. Taken together, our companion papers show that FAV acts via lethal mutagenesis against ZIKV and highlight the host cell’s influence on the activation and antiviral activity of nucleoside analogues. Furthermore, the information gleaned from these companion papers can be applied to gain a more comprehensive understanding of the activity of nucleoside analogues and the impact of host cell factors against other viral infections for which we currently have no approved antiviral therapies. Full article

(This article belongs to the Special Issue Recent Advances in Antivirals for Emerging Viruses 2.0)

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15 pages, 1378 KiB

Open AccessArticle

Favipiravir Inhibits Zika Virus (ZIKV) Replication in HeLa Cells by Altering Viral Infectivity

by Evelyn J. Franco, Kaley C. Hanrahan and Ashley N. Brown

Microorganisms 2023, 11(5), 1097; https://doi.org/10.3390/microorganisms11051097 - 22 Apr 2023

Cited by 2 | Viewed by 1552

Abstract

This study aims to evaluate the antiviral potential of the nucleoside analogue favipiravir (FAV) against ZIKV, an arbovirus for which there are no approved antiviral therapies, in three human-derived cell lines. HeLa (cervical), SK-N-MC (neuronal), and HUH-7 (liver) cells were infected with ZIKV and exposed to different concentrations of FAV. Viral supernatant was sampled daily, and infectious viral burden was quantified by plaque assay. Changes in ZIKV infectivity were quantified by calculating specific infectivity. FAV-related toxicities were also assessed for each cell line in both infected and uninfected cells. Our results demonstrate that FAV activity was most pronounced in HeLa cells, as substantial declines in infectious titers and viral infectivity were observed in this cell type. The decline in infectious virus occurred in an exposure-dependent manner and was more pronounced as FAV exposure times increased. Additionally, toxicity studies showed that FAV was not toxic to any of the three cell lines and, surprisingly, caused substantial improvements in the viability of infected HeLa cells. Although SK-N-MC and HUH-7 cells were susceptible to FAV’s anti-ZIKV activity, similar effects on viral infectivity and improvements in cell viability with therapy were not observed. These results indicate that FAV’s ability to substantially alter viral infectivity is host cell specific and suggest that the robust antiviral effect observed in HeLa cells is mediated through drug-induced losses of viral infectivity. Full article

(This article belongs to the Special Issue Recent Advances in Antivirals for Emerging Viruses 2.0)

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11 pages, 1600 KiB

Open AccessArticle

A RNase P Ribozyme Inhibits Gene Expression and Replication of Hepatitis B Virus in Cultured Cells

by Bin Yan, Yujun Liu, Yuan-Chuan Chen and Fenyong Liu

Microorganisms 2023, 11(3), 654; https://doi.org/10.3390/microorganisms11030654 - 3 Mar 2023

Cited by 4 | Viewed by 1949

Abstract

Hepatitis B virus (HBV), an international public health concern, is a leading viral cause of liver disease, such as hepatocellular carcinoma. Sequence-specific ribozymes derived from ribonuclease P (RNase P) catalytic RNA are being explored for gene targeting applications. In this study, we engineered an active RNase P ribozyme, M1-S-A, targeting the overlapping region of HBV S mRNA, pre-S/L mRNA, and pregenomic RNA (pgRNA), all deemed essential for viral infection. Ribozyme M1-S-A cleaved the S mRNA sequence efficiently in vitro. We studied the effect of RNase P ribozyme on HBV gene expression and replication using the human hepatocyte HepG2.2.15 culture model that harbors an HBV genome and supports HBV replication. In these cultured cells, the expression of M1-S-A resulted in a reduction of more than 80% in both HBV RNA and protein levels and an inhibition of about 300-fold in the capsid-associated HBV DNA levels when compared to the cells that did not express any ribozymes. In control experiments, cells expressing an inactive control ribozyme displayed little impact on HBV RNA and protein levels, and on capsid-associated viral DNA levels. Our study signifies that RNase P ribozyme can suppress HBV gene expression and replication, implying the promise of RNase P ribozymes for anti-HBV therapy. Full article

(This article belongs to the Special Issue Recent Advances in Antivirals for Emerging Viruses 2.0)

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15 pages, 2743 KiB

Open AccessArticle

Discovery of a 2′-Fluoro,2′-Bromouridine Phosphoramidate Prodrug Exhibiting Anti-Yellow Fever Virus Activity in Culture and in Mice

by Julia C. LeCher, Keivan Zandi, Vivian Vasconcelos Costa, Franck Amblard, Sijia Tao, Dharmeshkumar Patel, Sujin Lee, Felipe Rocha da Silva Santos, Matheus Rodrigues Goncalves, Celso Martins Queroz-Junior, Fernanda Martins Marim, Katie Musall, Shu Ling Goh, Tamara McBrayer, Jessica Downs-Bowen, Ramyani De, Niloufar Azadi, James Kohler, Mauro Martins Teixeira and Raymond F. Schinazi

Microorganisms 2022, 10(11), 2098; https://doi.org/10.3390/microorganisms10112098 - 22 Oct 2022

Cited by 2 | Viewed by 2234

Abstract

Yellow fever virus (YFV) is a potentially lethal, zoonotic, blood-borne flavivirus transmitted to humans and non-human primates by mosquitoes. Owing to multiple deadly epidemics, the WHO classifies YFV as a “high impact, high threat disease” with resurgent epidemic potential. At present, there are no approved antiviral therapies to combat YFV infection. Herein we report on 2′-halogen-modified nucleoside analogs as potential anti-YFV agents. Of 11 compounds evaluated, three showed great promise with low toxicity, high intracellular metabolism into the active nucleoside triphosphate form, and sub-micromolar anti-YFV activity. Notably, we investigated a 2′-fluoro,2′-bromouridine phosphate prodrug (C9), a known anti-HCV agent with good stability in human blood and favorable metabolism. Predictive modeling revealed that C9 could readily bind the active site of the YFV RdRp, conferring its anti-YFV activity. C9 displayed potent anti-YFV activity in primary human macrophages, 3D hepatocyte spheroids, and in mice. In an A129 murine model, shortly after infection, C9 significantly reduced YFV replication and protected against YFV-induced liver inflammation and pathology with no adverse effects. Collectively, this work identifies a potent new anti-YFV agent with strong therapeutic promise. Full article

(This article belongs to the Special Issue Recent Advances in Antivirals for Emerging Viruses 2.0)

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Review

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26 pages, 808 KiB

Open AccessReview

Strategies for the Management of Spike Protein-Related Pathology

by Matthew T. J. Halma, Christof Plothe, Paul Marik and Theresa A. Lawrie

Microorganisms 2023, 11(5), 1308; https://doi.org/10.3390/microorganisms11051308 - 17 May 2023

Cited by 4 | Viewed by 48717

Abstract

In the wake of the COVID-19 crisis, a need has arisen to prevent and treat two related conditions, COVID-19 vaccine injury and long COVID-19, both of which can trace at least part of their aetiology to the spike protein, which can cause harm through several mechanisms. One significant mechanism of harm is vascular, and it is mediated by the spike protein, a common element of the COVID-19 illness, and it is related to receiving a COVID-19 vaccine. Given the significant number of people experiencing these two related conditions, it is imperative to develop treatment protocols, as well as to consider the diversity of people experiencing long COVID-19 and vaccine injury. This review summarizes the known treatment options for long COVID-19 and vaccine injury, their mechanisms, and their evidentiary basis. Full article

(This article belongs to the Special Issue Recent Advances in Antivirals for Emerging Viruses 2.0)

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34 pages, 1390 KiB

Open AccessReview

A Rationale and Approach to the Development of Specific Treatments for HIV Associated Neurocognitive Impairment

by Aaron Scanlan, Zhan Zhang, Rajeth Koneru, Monica Reece, Christina Gavegnano, Albert M. Anderson and William Tyor

Microorganisms 2022, 10(11), 2244; https://doi.org/10.3390/microorganisms10112244 - 12 Nov 2022

Cited by 3 | Viewed by 2688

Abstract

Neurocognitive impairment (NCI) associated with HIV infection of the brain impacts a large proportion of people with HIV (PWH) regardless of antiretroviral therapy (ART). While the number of PWH and severe NCI has dropped considerably with the introduction of ART, the sole use of ART is not sufficient to prevent or arrest NCI in many PWH. As the HIV field continues to investigate cure strategies, adjunctive therapies are greatly needed. HIV imaging, cerebrospinal fluid, and pathological studies point to the presence of continual inflammation, and the presence of HIV RNA, DNA, and proteins in the brain despite ART. Clinical trials exploring potential adjunctive therapeutics for the treatment of HIV NCI over the last few decades have had limited success. Ideally, future research and development of novel compounds need to address both the HIV replication and neuroinflammation associated with HIV infection in the brain. Brain mononuclear phagocytes (MPs) are the primary instigators of inflammation and HIV protein expression; therefore, adjunctive treatments that act on MPs, such as immunomodulating agents, look promising. In this review, we will highlight recent developments of innovative therapies and discuss future approaches for HIV NCI treatment. Full article

(This article belongs to the Special Issue Recent Advances in Antivirals for Emerging Viruses 2.0)

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22 pages, 567 KiB

Open AccessReview

Inhibitors of Nucleotide Biosynthesis as Candidates for a Wide Spectrum of Antiviral Chemotherapy

by Claudia Soledad Sepúlveda, Cybele Carina García and Elsa Beatriz Damonte

Microorganisms 2022, 10(8), 1631; https://doi.org/10.3390/microorganisms10081631 - 12 Aug 2022

Cited by 13 | Viewed by 3566

Abstract

Emerging and re-emerging viruses have been a challenge in public health in recent decades. Host-targeted antivirals (HTA) directed at cellular molecules or pathways involved in virus multiplication represent an interesting strategy to combat viruses presently lacking effective chemotherapy. HTA could provide a wide range of agents with inhibitory activity against current and future viruses that share similar host requirements and reduce the possible selection of antiviral-resistant variants. Nucleotide metabolism is one of the more exploited host metabolic pathways as a potential antiviral target for several human viruses. This review focuses on the antiviral properties of the inhibitors of pyrimidine and purine nucleotide biosynthesis, with an emphasis on the rate-limiting enzymes dihydroorotate dehydrogenase (DHODH) and inosine monophosphate dehydrogenase (IMPDH) for which there are old and new drugs active against a broad spectrum of pathogenic viruses. Full article

(This article belongs to the Special Issue Recent Advances in Antivirals for Emerging Viruses 2.0)

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13 pages, 847 KiB

Open AccessReview

Viral Vector Vaccine Development and Application during the COVID-19 Pandemic

by Shaofeng Deng, Hui Liang, Pin Chen, Yuwan Li, Zhaoyao Li, Shuangqi Fan, Keke Wu, Xiaowen Li, Wenxian Chen, Yuwei Qin, Lin Yi and Jinding Chen

Microorganisms 2022, 10(7), 1450; https://doi.org/10.3390/microorganisms10071450 - 18 Jul 2022

Cited by 48 | Viewed by 12436

Abstract

With the accumulation of mutations in SARS-CoV-2 and the continuous emergence of new variants, the importance of developing safer and effective vaccines has become more prominent in combating the COVID-19 pandemic. Both traditional and genetically engineered vaccines have contributed to the prevention and control of the pandemic. However, in recent years, the trend of vaccination research has gradually transitioned from traditional to genetically engineered vaccines, with the development of viral vector vaccines attracting increasing attention. Viral vector vaccines have several unique advantages compared to other vaccine platforms. The spread of Omicron has also made the development of intranasal viral vector vaccines more urgent, as the infection site of Omicron is more prominent in the upper respiratory tract. Therefore, the present review focuses on the development of viral vector vaccines and their application during the COVID-19 pandemic. Full article

(This article belongs to the Special Issue Recent Advances in Antivirals for Emerging Viruses 2.0)

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23 pages, 820 KiB

Open AccessReview

The Advances of Broad-Spectrum and Hot Anti-Coronavirus Drugs

by Sen Zeng, Yuwan Li, Wenhui Zhu, Zipeng Luo, Keke Wu, Xiaowen Li, Yiqi Fang, Yuwei Qin, Wenxian Chen, Zhaoyao Li, Linke Zou, Xiaodi Liu, Lin Yi and Shuangqi Fan

Microorganisms 2022, 10(7), 1294; https://doi.org/10.3390/microorganisms10071294 - 26 Jun 2022

Cited by 4 | Viewed by 3344

Abstract

Coronaviruses, mainly including severe acute respiratory syndrome virus, severe acute respiratory syndrome coronavirus 2, Middle East respiratory syndrome virus, human coronavirus OC43, chicken infectious bronchitis virus, porcine infectious gastroenteritis virus, porcine epidemic diarrhea virus, and murine hepatitis virus, can cause severe diseases in humans and livestock. The severe acute respiratory syndrome coronavirus 2 is infecting millions of human beings with high morbidity and mortality worldwide, and the multiplicity of swine epidemic diarrhea coronavirus in swine suggests that coronaviruses seriously jeopardize the safety of public health and that therapeutic intervention is urgently needed. Currently, the most effective methods of prevention and control for coronaviruses are vaccine immunization and pharmacotherapy. However, the emergence of mutated viruses reduces the effectiveness of vaccines. In addition, vaccine developments often lag behind, making it difficult to put them into use early in the outbreak. Therefore, it is meaningful to screen safe, cheap, and broad-spectrum antiviral agents for coronaviruses. This review systematically summarizes the mechanisms and state of anti-human and porcine coronavirus drugs, in order to provide theoretical support for the development of anti-coronavirus drugs and other antivirals. Full article

(This article belongs to the Special Issue Recent Advances in Antivirals for Emerging Viruses 2.0)

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