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viruses Review Broad-Spectrum Antiviral Strategies and Nucleoside Analogues Robert J. Geraghty 1 , Matthew T. Aliota 2 and Laurent F. Bonnac 1,* 1 Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA; [email protected] 2 Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA; [email protected] * Correspondence: [email protected] Abstract: The emergence or re-emergence of viruses with epidemic and/or pandemic potential, such as Ebola, Zika, Middle East Respiratory Syndrome (MERS-CoV), Severe Acute Respiratory Syndrome Coronavirus 1 and 2 (SARS and SARS-CoV-2) viruses, or new strains of influenza represents sig- nificant human health threats due to the absence of available treatments. Vaccines represent a key answer to control these viruses. However, in the case of a public health emergency, vaccine develop- ment, safety, and partial efficacy concerns may hinder their prompt deployment. Thus, developing broad-spectrum antiviral molecules for a fast response is essential to face an outbreak crisis as well as for bioweapon countermeasures. So far, broad-spectrum antivirals include two main categories: the family of drugs targeting the host-cell machinery essential for virus infection and replication, and the family of drugs directly targeting viruses. Among the molecules directly targeting viruses, nucleoside analogues form an essential class of broad-spectrum antiviral drugs. In this review, we will discuss the interest for broad-spectrum antiviral strategies and their limitations, with an emphasis on virus-targeted, broad-spectrum, antiviral nucleoside analogues and their mechanisms of action. Keywords: broad-spectrum antivirals; lethal mutagenesis; chain terminator; nucleoside analogues Citation: Geraghty, R.J.; Aliota, M.T.; Bonnac, L.F. Broad-Spectrum Antiviral Strategies and Nucleoside Analogues. Viruses 2021, 13, 667. https://doi.org/10.3390/v13040667 1. The Interest of Broad-Spectrum Antiviral Strategies Antiviral drug development has long focused on virus-specific approaches: the strat- Academic Editor: Cheng-Wen Lin egy to study a virus and identify a specific viral protein as a drug target in order to limit potential toxicity and to increase drug efficacy (Figure1). Virus-specific drug development Received: 18 March 2021 has also been favored as a way to simplify the drug discovery process compared to the Accepted: 12 April 2021 more complex design of broad-spectrum antivirals, which often require targeting critical Published: 13 April 2021 proteins belonging to different viruses or critical cellular processes used by different viruses. Virus-specific antiviral research remains a successful and essential strategy to combat viral Publisher’s Note: MDPI stays neutral infections [1]. However, a major obstacle to virus-specific drug development is the length with regard to jurisdictional claims in of the process, which, on average, takes more than a decade between research and drug published maps and institutional affil- approval [2]. Indeed, virus-specific drug development needs first to address fundamental iations. biology of the virus to find an appropriate target before moving to medicinal chemistry research, compounds screening, lead optimization, animal studies and eventual clinical trials. The time constraint for antiviral drug discovery has gradually become more impor- tant due to the increasing number of viral outbreaks that have recently and consecutively Copyright: © 2021 by the authors. afflicted our societies including Ebola virus [3], Middle East Respiratory Syndrome coron- Licensee MDPI, Basel, Switzerland. avirus MERS-CoV [4], Severe Acute Respiratory Syndrome Coronavirus 1 and 2 (SARS and This article is an open access article SARS-CoV-2) [5,6], new strains of influenza A virus [7] as well as dengue virus [8], Zika distributed under the terms and virus [9,10], West Nile virus [11] and Chikungunya virus [12]. Reasons for the increased conditions of the Creative Commons appearances of these outbreaks include increased population densities, forest fragmenta- Attribution (CC BY) license (https:// tion, intercontinental traveling, and climate change [13,14]. Regardless of their origins, the creativecommons.org/licenses/by/ recent and consecutive nature of these outbreaks highlight the challenges of virus-specific 4.0/). Viruses 2021, 13, 667. https://doi.org/10.3390/v13040667 https://www.mdpi.com/journal/viruses Viruses 2021, 13, x FOR PEER REVIEW 2 of 12 Viruses 2021, 13, 667 forest fragmentation, intercontinental traveling, and climate change [13,14]. Regardless 2of of 12 their origins, the recent and consecutive nature of these outbreaks highlight the challenges of virus-specific drug research for fast discovery of a therapeutic. Similarly, vaccine de- drugvelopment, research although for fast discoveryparticularly of relevant a therapeutic. to face Similarly,outbreaks vaccineand pandemics, development, also requires although particularlya significant relevant development to face time outbreaks to ensure and the pandemics, efficacy and also safety requires of the avaccine significant [15]. Re- devel- opmentpurposing time antiviral to ensure drugs, the efficacythe strategy and safetyto evaluate of the approved vaccine [15drugs]. Re-purposing for known viruses antiviral drugs,against the new strategy viruses to is evaluate highly advantageous approved drugs in terms for known of reducing viruses cost against and saving new viruses time, is highlyand has advantageous therefore been in termsan essential of reducing component cost and of savingemergency time, responses and has thereforeduring public been an health crisis [16]. essential component of emergency responses during public health crisis [16]. Virus replication cycle Antiviral strategies Figure 1. Virus replication cycle and antiviral strategies. Figure 1. Virus replication cycle and antiviral strategies. Drug re-purposing is advantageous in that the initial part of the drug discovery Drug re-purposing is advantageous in that the initial part of the drug discovery pro- process can be bypassed including medicinal chemistry research and lead optimization as cess can be bypassed including medicinal chemistry research and lead optimization as well as the safety evaluation in phase 1 clinical trials, therefore reducing considerably the well as the safety evaluation in phase 1 clinical trials, therefore reducing considerably the research and development time. Yet, re-purposing antiviral drugs successfully is inherently research and development time. Yet, re-purposing antiviral drugs successfully is inher- dependentently dependent on the on ability the ability of an antiviralof an antiviral drug drug to be to active be active against against multiple multiple viruses, viruses, hence, thehence, need the of need a broad-spectrum of a broad-spectrum antiviral antivira effect.l Historically,effect. Historically, broad-spectrum broad-spectrum antivirals antivi- have firstrals beenhave discoveredfirst been discovered by serendipity by serendip throughity through simple screeningsimple screening assays againstassays against different virusesdifferent rather viruses than rather through than through a deliberate a deliberate strategy strategy to design to design drugs drugs to display to display a broad- a spectrumbroad-spectrum antiviral antiviral effect [effect17,18 ][17,18] for ribavirin for ribavirin or more or more recently recently with with antibiotic antibiotic derivatives deriv- withatives antiviral with antiviral properties properties [19,20]. [19,20]. From theseFrom initial these antiviralinitial antiviral drug evaluations drug evaluations emerged patternsemerged of patterns drugs withof drugs similar with biological similar biologic effects.al effects. Broad-spectrum Broad-spectrum antiviral antiviral drugs drugs can be classifiedcan be classified into two into main two categories; main categories; first, drugs first, thatdrugs affect that the affect host-cell the host-cell machinery machinery essential foressential the infection for the andinfection replication and replication of different of different viruses, viruses, and second; and second; drugs drugs targeting targeting viruses directly.viruses directly. Both families Both families of broad-spectrum of broad-spec antiviraltrum antiviral drugs drugs (e.g., (e.g., host-targeted host-targeted or virus-or targetedvirus-targeted broad-spectrum broad-spectrum antivirals) antivirals) present present advantages, advantages, and disadvantagesand disadvantages (Table (Table1). 1). Table 1. Pros and cons of different antiviral strategies, virus-specific antiviral strategies, host-targeted and virus-targeted broad-spectrum antiviral strategies. Broad-Spectrum Antiviral Strategies Virus-Specific Antiviral Strategies Host-Targeted Virus-Targeted Pros: Pros: Pros: - Proven efficacy - Host proteins broadly required by viruses - Less potential for toxicity compared to - Easier design, one viral target - Demonstrated antiviral effect host-targeted strategies. - Relative safety compared to other strategies - Higher barrier to drug resistance development - Potential for repurposing Cons: Cons: Cons: - Narrow application - More complex design - Not selective - Low barrier to drug resistance development - Limited examples of broad-spectrum - Potential for toxicity - Long development time antiviral drugs Viruses 2021, 13, 667 3 of 12 2. Host-Targeted Antiviral Strategies Host-targeted antiviral strategies, reviewed here [21,22], feature a wide range of host
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  • Lethal Mutagenesis of Hepatitis C Virus Induced by Favipiravir

    Lethal Mutagenesis of Hepatitis C Virus Induced by Favipiravir

    RESEARCH ARTICLE Lethal Mutagenesis of Hepatitis C Virus Induced by Favipiravir Ana I. de AÂ vila1, Isabel Gallego1,2, Maria Eugenia Soria3, Josep Gregori2,3,4, Josep Quer2,3,5, Juan Ignacio Esteban2,3,5, Charles M. Rice6, Esteban Domingo1,2*, Celia Perales1,2,3* 1 Centro de BiologõÂa Molecular ªSevero Ochoaº (CSIC-UAM), Consejo Superior de Investigaciones CientõÂficas (CSIC), Campus de Cantoblanco, 28049, Madrid, Spain, 2 Centro de InvestigacioÂn BiomeÂdica en Red de Enfermedades HepaÂticas y Digestivas (CIBERehd), Barcelona, Spain, 3 Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d'Hebron Institut de Recerca-Hospital Universitari Vall d a11111 ÂHebron, (VHIR-HUVH), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain, 4 Roche Diagnostics, S.L., Sant Cugat del ValleÂs, Spain, 5 Universitat AutoÂnoma de Barcelona, Barcelona, Spain, 6 Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, United States of America * [email protected] (ED); [email protected] (CP) OPEN ACCESS Abstract Citation: de AÂvila AI, Gallego I, Soria ME, Gregori J, Quer J, Esteban JI, et al. (2016) Lethal Lethal mutagenesis is an antiviral approach that consists in extinguishing a virus by an Mutagenesis of Hepatitis C Virus Induced by excess of mutations acquired during replication in the presence of a mutagen. Here we Favipiravir. PLoS ONE 11(10): e0164691. show that favipiravir (T-705) is a potent mutagenic agent for hepatitis C virus (HCV) during doi:10.1371/journal.pone.0164691 its replication in human hepatoma cells. T-705 leads to an excess of G ! A and C ! U tran- Editor: Ming-Lung Yu, Kaohsiung Medical sitions in the mutant spectrum of preextinction HCV populations.