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A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Antimicrobial Agents and Resistance".

Deadline for manuscript submissions: closed (20 September 2021) | Viewed by 49032

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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,

The emergence of Covid-19 is a reminder that new transmissible viruses have a potential global social, health, and economic impact. Current biological tools (including rapid and efficient cloning and sequencing) have advanced basic scientific efforts to identify 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 exponentially expanded, resulting in vast libraries of compounds for screening direct antiviral activity. This Special issue will highlight recent advances in antiviral drug developments, including:

1) direct 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 (11 papers)

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Research

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15 pages, 7130 KiB

Open AccessArticle

Tilorone-Dihydrochloride Protects against Rift Valley Fever Virus Infection and Disease in the Mouse Model

by Kendra N. Johnson, Birte Kalveram, Jennifer K. Smith, Lihong Zhang, Terry Juelich, Colm Atkins, Tetsuro Ikegami and Alexander N. Freiberg

Microorganisms 2022, 10(1), 92; https://doi.org/10.3390/microorganisms10010092 - 31 Dec 2021

Cited by 3 | Viewed by 2330

Abstract

Rift Valley fever (RVF) is a mosquito-borne zoonotic disease endemic to Africa and the Middle East that can affect humans and ruminant livestock. Currently, there are no approved vaccines or therapeutics for the treatment of severe RVF disease in humans. Tilorone-dihydrochloride (Tilorone) is a broad-spectrum antiviral candidate that has previously shown efficacy against a wide range of DNA and RNA viruses, and which is clinically utilized for the treatment of respiratory infections in Russia and other Eastern European countries. Here, we evaluated the antiviral activity of Tilorone against Rift Valley fever virus (RVFV). In vitro, Tilorone inhibited both vaccine (MP-12) and virulent (ZH501) strains of RVFV at low micromolar concentrations. In the mouse model, treatment with Tilorone significantly improved survival outcomes in BALB/c mice challenged with a lethal dose of RVFV ZH501. Treatment with 30 mg/kg/day resulted in 80% survival when administered immediately after infection. In post-exposure prophylaxis, Tilorone resulted in 30% survival at one day after infection when administered at 45 mg/kg/day. These findings demonstrate that Tilorone has potent antiviral efficacy against RVFV infection in vitro and in vivo and supports further development of Tilorone as a potential antiviral therapeutic for treatment of RVFV infection. Full article

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

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10 pages, 943 KiB

Open AccessCommunication

Favipiravir Does Not Inhibit Chikungunya Virus Replication in Mosquito Cells and Aedes aegypti Mosquitoes

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

Microorganisms 2021, 9(5), 944; https://doi.org/10.3390/microorganisms9050944 - 27 Apr 2021

Cited by 4 | Viewed by 2583

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. Full article

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

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10 pages, 1684 KiB

Open AccessArticle

Baicalein and Baicalin Inhibit SARS-CoV-2 RNA-Dependent-RNA Polymerase

by Keivan Zandi, Katie Musall, Adrian Oo, Dongdong Cao, Bo Liang, Pouya Hassandarvish, Shuiyun Lan, Ryan L. Slack, Karen A. Kirby, Leda Bassit, Franck Amblard, Baek Kim, Sazaly AbuBakar, Stefan G. Sarafianos and Raymond F. Schinazi

Microorganisms 2021, 9(5), 893; https://doi.org/10.3390/microorganisms9050893 - 22 Apr 2021

Cited by 98 | Viewed by 7502

Abstract

Coronavirus Disease 2019 (COVID-19) is a deadly emerging infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Because SARS-CoV-2 is easily transmitted through the air and has a relatively long incubation time, COVID-19 has rapidly developed into a global pandemic. As there are no antiviral agents for the prevention and treatment of this severe pathogen except for remdesivir, development of antiviral therapies to treat infected individuals remains highly urgent. Here, we showed that baicalein and baicalin exhibited significant antiviral activity against SARS-CoV-2, the causative agent of COVID-19 through in vitro studies. Our data through cell-based and biochemical studies showed that both compounds act as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitors directly and inhibit the activity of the SARS-CoV-2 RdRp, but baicalein was more potent. We also showed specific binding of baicalein to the SARS-CoV-2 RdRp, making it a potential candidate for further studies towards therapeutic development for COVID-19 as a selective non-nucleoside polymerase inhibitor. Full article

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

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12 pages, 1002 KiB

Open AccessArticle

Repurposing Drugs for Mayaro Virus: Identification of EIDD-1931, Favipiravir and Suramin as Mayaro Virus Inhibitors

by Lana Langendries, Rana Abdelnabi, Johan Neyts and Leen Delang

Microorganisms 2021, 9(4), 734; https://doi.org/10.3390/microorganisms9040734 - 31 Mar 2021

Cited by 17 | Viewed by 3441

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-N⁴-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. Full article

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

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12 pages, 1420 KiB

Open AccessArticle

Structure-Based Virtual Screening: Identification of a Novel NS2B-NS3 Protease Inhibitor with Potent Antiviral Activity against Zika and Dengue Viruses

by Hye Jin Shin, Mi-Hwa Kim, Joo-Youn Lee, Insu Hwang, Gun Young Yoon, Hae Soo Kim, Young-Chan Kwon, Dae-Gyun Ahn, Kyun-Do Kim, Bum-Tae Kim, Seong-Jun Kim and Chonsaeng Kim

Microorganisms 2021, 9(3), 545; https://doi.org/10.3390/microorganisms9030545 - 6 Mar 2021

Cited by 21 | Viewed by 4060

Abstract

Zika virus (ZIKV), which is associated with severe diseases in humans, has spread rapidly and globally since its emergence. ZIKV and dengue virus (DENV) are closely related, and antibody-dependent enhancement (ADE) of infection between cocirculating ZIKV and DENV may exacerbate disease. Despite these serious threats, there are currently no approved antiviral drugs against ZIKV and DENV. The NS2B-NS3 viral protease is an attractive antiviral target because it plays a pivotal role in polyprotein cleavage, which is required for viral replication. Thus, we sought to identify novel inhibitors of the NS2B-NS3 protease. To that aim, we performed structure-based virtual screening using 467,000 structurally diverse chemical compounds. Then, a fluorescence-based protease inhibition assay was used to test whether the selected candidates inhibited ZIKV protease activity. Among the 123 candidate inhibitors selected from virtual screening, compound 1 significantly inhibited ZIKV NS2B-NS3 protease activity in vitro. In addition, compound 1 effectively inhibited ZIKV and DENV infection of human cells. Molecular docking analysis suggested that compound 1 binds to the NS2B-NS3 protease of ZIKV and DENV. Thus, compound 1 could be used as a new therapeutic option for the development of more potent antiviral drugs against both ZIKV and DENV, reducing the risks of ADE. Full article

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

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16 pages, 2083 KiB

Open AccessArticle

Combination Regimens of Favipiravir Plus Interferon Alpha Inhibit Chikungunya Virus Replication in Clinically Relevant Human Cell Lines

by Evelyn J. Franco, Xun Tao, Kaley C. Hanrahan, Jieqiang Zhou, Jürgen B. Bulitta and Ashley N. Brown

Microorganisms 2021, 9(2), 307; https://doi.org/10.3390/microorganisms9020307 - 2 Feb 2021

Cited by 7 | Viewed by 2582

Abstract

Chikungunya virus (CHIKV) is an alphavirus associated with a broad tissue tropism for which no antivirals or vaccines are approved. This study evaluated the antiviral potential of favipiravir (FAV), interferon-alpha (IFN), and ribavirin (RBV) against CHIKV as mono- and combination-therapy in cell lines that are clinically relevant to human infection. Cells derived from human connective tissue (HT-1080), neurons (SK-N-MC), and skin (HFF-1) were infected with CHIKV and treated with different concentrations of FAV, IFN, or RBV. Viral supernatant was sampled daily and the burden was quantified by plaque assay on Vero cells. FAV and IFN were the most effective against CHIKV on various cell lines, suppressing the viral burden at clinically achievable concentrations; although the degree of antiviral activity was heavily influenced by cell type. RBV was not effective and demonstrated substantial toxicity, indicating that it is not a feasible candidate for CHIKV. The combination of FAV and IFN was then assessed on all cell lines. Combination therapy enhanced antiviral activity in HT-1080 and SK-N-MC cells, but not in HFF-1 cells. We developed a pharmacokinetic/pharmacodynamic model that described the viral burden and inhibitory antiviral effect. Simulations from this model predicted clinically relevant concentrations of FAV plus IFN completely suppressed CHIKV replication in HT-1080 cells, and considerably slowed down the rate of viral replication in SK-N-MC cells. The model predicted substantial inhibition of viral replication by clinical IFN regimens in HFF-1 cells. Our results highlight the antiviral potential of FAV and IFN combination regimens against CHIKV in clinically relevant cell types. Full article

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

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8 pages, 464 KiB

Open AccessCommunication

SARS-CoV-2 Inhibition by Sulfonated Compounds

by Matteo Gasbarri, Philip V’kovski, Giulia Torriani, Volker Thiel, Francesco Stellacci, Caroline Tapparel and Valeria Cagno

Microorganisms 2020, 8(12), 1894; https://doi.org/10.3390/microorganisms8121894 - 30 Nov 2020

Cited by 21 | Viewed by 4354

Abstract

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) depends on angiotensin converting enzyme 2 (ACE2) for cellular entry, but it might also rely on attachment receptors such as heparan sulfates. Several groups have recently demonstrated an affinity of the SARS-CoV2 spike protein for heparan sulfates and a reduced binding to cells in the presence of heparin or heparinase treatment. Here, we investigated the inhibitory activity of several sulfated and sulfonated molecules, which prevent interaction with heparan sulfates, against vesicular stomatitis virus (VSV)-pseudotyped-SARS-CoV-2 and the authentic SARS-CoV-2. Sulfonated cyclodextrins and nanoparticles that have recently shown broad-spectrum non-toxic virucidal activity against many heparan sulfates binding viruses showed inhibitory activity in the micromolar and nanomolar ranges, respectively. In stark contrast with the mechanisms that these compounds present for these other viruses, the inhibition against SARS-CoV-2 was found to be simply reversible. Full article

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

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19 pages, 5592 KiB

Open AccessArticle

Identification of an Antiviral Compound from the Pandemic Response Box that Efficiently Inhibits SARS-CoV-2 Infection In Vitro

by Melle Holwerda, Philip V’kovski, Manon Wider, Volker Thiel and Ronald Dijkman

Microorganisms 2020, 8(12), 1872; https://doi.org/10.3390/microorganisms8121872 - 26 Nov 2020

Cited by 23 | Viewed by 5913

Abstract

With over 50 million currently confirmed cases worldwide, including more than 1.3 million deaths, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has a major impact on the economy and health care system. Currently, limited prophylactic or therapeutic intervention options are available against SARS-CoV-2. In this study, 400 compounds from the antimicrobial “pandemic response box” library were screened for inhibiting properties against SARS-CoV-2. An initial screen on Vero E6 cells identified five compounds that inhibited SARS-CoV-2 replication. However, validation of the selected hits in a human lung cell line highlighted that only a single compound, namely Retro-2.1, efficiently inhibited SARS-CoV-2 replication. Additional analysis revealed that the antiviral activity of Retro-2.1 occurs at a post-entry stage of the viral replication cycle. Combined, these data demonstrate that stringent in vitro screening of preselected compounds in multiple cell lines refines the rapid identification of new potential antiviral candidate drugs targeting SARS-CoV-2. Full article

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

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Review

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16 pages, 806 KiB

Open AccessReview

Possible Targets of Pan-Coronavirus Antiviral Strategies for Emerging or Re-Emerging Coronaviruses

by Xue Li, Liying Zhang, Si Chen, Hongsheng Ouyang and Linzhu Ren

Microorganisms 2021, 9(7), 1479; https://doi.org/10.3390/microorganisms9071479 - 10 Jul 2021

Cited by 11 | Viewed by 4697

Abstract

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which caused Coronaviruses Disease 2019 (COVID-19) and a worldwide pandemic, is the seventh human coronavirus that has been cross-transmitted from animals to humans. It can be predicted that with continuous contact between humans and animals, more viruses will spread from animals to humans. Therefore, it is imperative to develop universal coronavirus or pan-coronavirus vaccines or drugs against the next coronavirus pandemic. However, a suitable target is critical for developing pan-coronavirus antivirals against emerging or re-emerging coronaviruses. In this review, we discuss the latest progress of possible targets of pan-coronavirus antiviral strategies for emerging or re-emerging coronaviruses, including targets for pan-coronavirus inhibitors and vaccines, which will provide prospects for the current and future research and treatment of the disease. Full article

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

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17 pages, 1078 KiB

Open AccessReview

Anti-Classical Swine Fever Virus Strategies

by Jindai Fan, Yingxin Liao, Mengru Zhang, Chenchen Liu, Zhaoyao Li, Yuwan Li, Xiaowen Li, Keke Wu, Lin Yi, Hongxing Ding, Mingqiu Zhao, Shuangqi Fan and Jinding Chen

Microorganisms 2021, 9(4), 761; https://doi.org/10.3390/microorganisms9040761 - 6 Apr 2021

Cited by 17 | Viewed by 6411

Abstract

Classical swine fever (CSF), caused by CSF virus (CSFV), is a highly contagious swine disease with high morbidity and mortality, which has caused significant economic losses to the pig industry worldwide. Biosecurity measures and vaccination are the main methods for prevention and control of CSF since no specific drug is available for the effective treatment of CSF. Although a series of biosecurity and vaccination strategies have been developed to curb the outbreak events, it is still difficult to eliminate CSF in CSF-endemic and re-emerging areas. Thus, in addition to implementing enhanced biosecurity measures and exploring more effective CSF vaccines, other strategies are also needed for effectively controlling CSF. Currently, more and more research about anti-CSFV strategies was carried out by scientists, because of the great prospects and value of anti-CSFV strategies in the prevention and control of CSF. Additionally, studies on anti-CSFV strategies could be used as a reference for other viruses in the Flaviviridae family, such as hepatitis C virus, dengue virus, and Zika virus. In this review, we aim to summarize the research on anti-CSFV strategies. In detail, host proteins affecting CSFV replication, drug candidates with anti-CSFV effects, and RNA interference (RNAi) targeting CSFV viral genes were mentioned and the possible mechanisms related to anti-CSFV effects were also summarized. Full article

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

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21 pages, 1477 KiB

Open AccessReview

Convalescent Plasma against COVID-19: A Broad-Spectrum Therapeutic Approach for Emerging Infectious Diseases

by Marijn Thijssen, Timothy Devos, Hanieh-Sadat Ejtahed, Samad Amini-Bavil-Olyaee, Ali Akbar Pourfathollah and Mahmoud Reza Pourkarim

Microorganisms 2020, 8(11), 1733; https://doi.org/10.3390/microorganisms8111733 - 5 Nov 2020

Cited by 16 | Viewed by 3735

Abstract

In the lack of an effective vaccine and antiviral treatment, convalescent plasma (CP) has been a promising therapeutic approach in past pandemics. Accumulating evidence in the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic corroborates the safety of CP therapy and preliminary data underline the potential efficacy. Recently, the Food and Drug Administration (FDA) permitted CP therapy for coronavirus disease 2019 (COVID-19) patients under the emergency use authorization, albeit additional clinical studies are still needed. The imminent threat of a second or even multiple waves of COVID-19 has compelled health authorities to delineate and calibrate a feasible preparedness algorithm for deploying CP as an immediate therapeutic intervention. The success of preparedness programs depends on the interdisciplinary actions of multiple actors in politics, science, and healthcare. In this review, we evaluate the current status of CP therapy for COVID-19 patients and address the challenges that confront the implementation of CP. Finally, we propose a pandemic preparedness framework for future waves of the COVID-19 pandemic and unknown pathogen outbreaks. Full article

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

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