Advances in Antiviral Agents against SARS-CoV-2 and Its Variants

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 (30 April 2023) | Viewed by 18973

Special Issue Editors


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Guest Editor
Dipartimento di Scienze della Vita e dell’Ambiente, University of Cagliari, Monserrato, 09042 Cagliari, CA, Italy
Interests: severe acute respiratory syndrome coronaviruses (SARS-CoV-2, SARS-CoV-1); Middle East respiratory syndrome coronaviruses (MERS-CoV); human immunodeficiency virus (HIV-1); hepatitis C virus; ebola virus; endogenous retroviruses; viral enzymes; inhibition and characterization of the mechanism of action of different viral targets
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, 80138 Napoli, NA, Italy
Interests: medicinal chemistry; synthetic organic chemistry; antiviral agents; drug design; protease inhibitors polymerase inhibitors; peptidomimetics; RNA virus; flavivirus; hepatitis C virus; coronavirus (SARS-CoV-2 and others)
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with 610 million reported cases and 6.5 million deaths, represents the worst pandemic in the last 100 years. Since 2020, in order to find effective treatments that can contain and limit infections, the scientific community has stepped up efforts to identify cures for COVID-19 at an unprecedented speed, with huge achievements being made in molecular virology, biological screening platforms, and drug discovery. In parallel with the search for drugs, several vaccines have been validated, which have proven effective in containing the spread of the pandemic. Despite the doses of vaccines, most of the population has been infected with the virus, often showing mild or severe symptoms of the infection. The third dose of the vaccine was needed to counter the emerging viral variants. Although part of the SARS-CoV-2 biology has been characterized in these two years and some drugs are approved for treatment, progress should continue to be made, with regard to antiviral agents against SARS-CoV-2 and its variants, for any infections caused by emerging and re-emerging viruses.

Researchers have been following different antiviral strategies targeting viral or host factors. The viral main protease and polymerase are currently the most known viral enzymes that being highly conserved hold promise for broad-spectrum inhibitors. Moreover, other nonstructural proteins essential for viral replication are still underexploited, such as the nsp13 helicase/NTPase, the nsp14/nsp16 methyltransferase, and the papain-like protease. In parallel, entry inhibitors targeting spike-mediated viral fusion or host endosomal or membrane proteases have demonstrated promising results in a preclinical setting. In general, the field of host-targeting agents represents a research area worthy of being explored.

This Special Issue is focused on Advances in Antiviral Agents against SARS-CoV-2 and its Variants and the development of new therapies, including antivirals and vaccine development.

Prof. Dr. Francesca Esposito
Dr. Rolando Cannalire
Guest Editors

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Keywords

  • SARS-CoV-2
  • antiviral agents
  • viral variants
  • therapies

Published Papers (10 papers)

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Editorial

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3 pages, 180 KiB  
Editorial
Special Issue “Advances in Antiviral Agents against SARS-CoV-2 and Its Variants”
by Francesca Esposito and Rolando Cannalire
Viruses 2023, 15(9), 1905; https://0-doi-org.brum.beds.ac.uk/10.3390/v15091905 - 10 Sep 2023
Viewed by 749
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with 770 million reported cases and around 7 million deaths, represents the worst pandemic in the last 100 years [...] Full article
(This article belongs to the Special Issue Advances in Antiviral Agents against SARS-CoV-2 and Its Variants)

Research

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12 pages, 1969 KiB  
Article
Synergistic Activity of Remdesivir–Nirmatrelvir Combination on a SARS-CoV-2 In Vitro Model and a Case Report
by Anna Gidari, Samuele Sabbatini, Elisabetta Schiaroli, Sabrina Bastianelli, Sara Pierucci, Chiara Busti, Lavinia Maria Saraca, Luca Capogrossi, Maria Bruna Pasticci and Daniela Francisci
Viruses 2023, 15(7), 1577; https://0-doi-org.brum.beds.ac.uk/10.3390/v15071577 - 19 Jul 2023
Cited by 5 | Viewed by 1341
Abstract
Background: This study aims to investigate the activity of the remdesivir–nirmatrelvir combination against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and to report a case of Coronavirus Disease 2019 (COVID-19) cured with this combination. Methods: A Vero E6 cell-based infection assay was used to [...] Read more.
Background: This study aims to investigate the activity of the remdesivir–nirmatrelvir combination against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and to report a case of Coronavirus Disease 2019 (COVID-19) cured with this combination. Methods: A Vero E6 cell-based infection assay was used to investigate the in vitro activity of the remdesivir–nirmatrelvir combination. The SARS-CoV-2 strains tested were 20A.EU1, BA.1 and BA.5. After incubation, a viability assay was performed. The supernatants were collected and used for viral titration. The Highest Single Agent (HSA) reference model was calculated. An HSA score >10 is considered synergic. Results: Remdesivir and nirmatrelvir showed synergistic activity at 48 and 72 h, with an HSA score of 52.8 and 28.6, respectively (p < 0.0001). These data were confirmed by performing supernatant titration and against the omicron variants: the combination reduced the viral titer better than the more active compound alone. An immunocompromised patient with prolonged and critical COVID-19 was successfully treated with remdesivir, nirmatrelvir/ritonavir, tixagevimab/cilgavimab and dexamethasone, with an excellent clinical–radiological response. However, she required further off-label prolonged therapy with nirmatrelvir/ritonavir until she tested negative. Conclusions: Remdesivir–nirmatrelvir combination has synergic activity in vitro. This combination may have a role in immunosuppressed patients with severe COVID-19 and prolonged viral shedding. Full article
(This article belongs to the Special Issue Advances in Antiviral Agents against SARS-CoV-2 and Its Variants)
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12 pages, 1705 KiB  
Article
SARS-CoV-2 Inactivation in Aerosol by Means of Radiated Microwaves
by Antonio Manna, Davide De Forni, Marco Bartocci, Nicola Pasculli, Barbara Poddesu, Florigio Lista, Riccardo De Santis, Donatella Amatore, Giorgia Grilli, Filippo Molinari, Alberto Sangiovanni Vincentelli and Franco Lori
Viruses 2023, 15(7), 1443; https://0-doi-org.brum.beds.ac.uk/10.3390/v15071443 - 27 Jun 2023
Cited by 2 | Viewed by 2266
Abstract
Coronaviruses are a family of viruses that cause disease in mammals and birds. In humans, coronaviruses cause infections on the respiratory tract that can be fatal. These viruses can cause both mild illnesses such as the common cold and lethal illnesses such as [...] Read more.
Coronaviruses are a family of viruses that cause disease in mammals and birds. In humans, coronaviruses cause infections on the respiratory tract that can be fatal. These viruses can cause both mild illnesses such as the common cold and lethal illnesses such as SARS, MERS, and COVID-19. Air transmission represents the principal mode by which people become infected by SARS-CoV-2. To reduce the risks of air transmission of this powerful pathogen, we devised a method of inactivation based on the propagation of electromagnetic waves in the area to be sanitized. We optimized the conditions in a controlled laboratory environment mimicking a natural airborne virus transmission and consistently achieved a 90% (tenfold) reduction of infectivity after a short treatment using a Radio Frequency (RF) wave emission with a power level that is safe for people according to most regulatory agencies, including those in Europe, USA, and Japan. To the best of our knowledge, this is the first time that SARS-CoV-2 has been shown to be inactivated through RF wave emission under conditions compatible with the presence of human beings and animals. Additional in-depth studies are warranted to extend the results to other viruses and to explore the potential implementation of this technology in different environmental conditions. Full article
(This article belongs to the Special Issue Advances in Antiviral Agents against SARS-CoV-2 and Its Variants)
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16 pages, 4247 KiB  
Article
DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action
by Daniela Iaconis, Francesca Caccuri, Candida Manelfi, Carmine Talarico, Antonella Bugatti, Federica Filippini, Alberto Zani, Rubina Novelli, Maria Kuzikov, Bernhard Ellinger, Philip Gribbon, Kristoffer Riecken, Francesca Esposito, Angela Corona, Enzo Tramontano, Andrea Rosario Beccari, Arnaldo Caruso and Marcello Allegretti
Viruses 2023, 15(5), 1128; https://0-doi-org.brum.beds.ac.uk/10.3390/v15051128 - 09 May 2023
Cited by 1 | Viewed by 1540
Abstract
During the COVID-19 pandemic, drug repurposing represented an effective strategy to obtain quick answers to medical emergencies. Based on previous data on methotrexate (MTX), we evaluated the anti-viral activity of several DHFR inhibitors in two cell lines. We observed that this class of [...] Read more.
During the COVID-19 pandemic, drug repurposing represented an effective strategy to obtain quick answers to medical emergencies. Based on previous data on methotrexate (MTX), we evaluated the anti-viral activity of several DHFR inhibitors in two cell lines. We observed that this class of compounds showed a significant influence on the virus-induced cytopathic effect (CPE) partly attributed to the intrinsic anti-metabolic activity of these drugs, but also to a specific anti-viral function. To elucidate the molecular mechanisms, we took advantage of our EXSCALATE platform for in-silico molecular modelling and further validated the influence of these inhibitors on nsp13 and viral entry. Interestingly, pralatrexate and trimetrexate showed superior effects in counteracting the viral infection compared to other DHFR inhibitors. Our results indicate that their higher activity is due to their polypharmacological and pleiotropic profile. These compounds can thus potentially give a clinical advantage in the management of SARS-CoV-2 infection in patients already treated with this class of drugs. Full article
(This article belongs to the Special Issue Advances in Antiviral Agents against SARS-CoV-2 and Its Variants)
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14 pages, 2403 KiB  
Article
Intranasal Boosting with Spike Fc-RBD of Wild-Type SARS-CoV-2 Induces Neutralizing Antibodies against Omicron Subvariants and Reduces Viral Load in the Nasal Turbinate of Mice
by Jian-Piao Cai, Cuiting Luo, Kun Wang, Hehe Cao, Lin-Lei Chen, Xiaojuan Zhang, Yuting Han, Feifei Yin, Anna Jinxia Zhang, Hin Chu, Shuofeng Yuan, Kin-Hang Kok, Kelvin Kai-Wang To, Honglin Chen, Zhiwei Chen, Dong-Yan Jin, Kwok-Yung Yuen and Jasper Fuk-Woo Chan
Viruses 2023, 15(3), 687; https://0-doi-org.brum.beds.ac.uk/10.3390/v15030687 - 06 Mar 2023
Cited by 4 | Viewed by 1976
Abstract
The emergence of new immune-evasive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and subvariants outpaces the development of vaccines specific against the dominant circulating strains. In terms of the only accepted immune correlate of protection, the inactivated whole-virion vaccine using wild-type SARS-CoV-2 [...] Read more.
The emergence of new immune-evasive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and subvariants outpaces the development of vaccines specific against the dominant circulating strains. In terms of the only accepted immune correlate of protection, the inactivated whole-virion vaccine using wild-type SARS-CoV-2 spike induces a much lower serum neutralizing antibody titre against the Omicron subvariants. Since the inactivated vaccine given intramuscularly is one of the most commonly used coronavirus disease 2019 (COVID-19) vaccines in developing regions, we tested the hypothesis that intranasal boosting after intramuscular priming would provide a broader level of protection. Here, we showed that one or two intranasal boosts with the Fc-linked trimeric spike receptor-binding domain from wild-type SARS-CoV-2 can induce significantly higher serum neutralizing antibodies against wild-type SARS-CoV-2 and the Omicron subvariants, including BA.5.2 and XBB.1, with a lower titre in the bronchoalveolar lavage of vaccinated Balb/c mice than vaccination with four intramuscular doses of inactivated whole virion vaccine. The intranasally vaccinated K18-hACE2-transgenic mice also had a significantly lower nasal turbinate viral load, suggesting a better protection of the upper airway, which is the predilected site of infection by Omicron subvariants. This intramuscular priming and intranasal boosting approach that achieves broader cross-protection against Omicron variants and subvariants may lengthen the interval required for changing the vaccine immunogen from months to years. Full article
(This article belongs to the Special Issue Advances in Antiviral Agents against SARS-CoV-2 and Its Variants)
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17 pages, 3063 KiB  
Article
Efficient CRISPR-Cas13d-Based Antiviral Strategy to Combat SARS-CoV-2
by Mouraya Hussein, Zaria Andrade dos Ramos, Monique A. Vink, Pascal Kroon, Zhenghao Yu, Luis Enjuanes, Sonia Zuñiga, Ben Berkhout and Elena Herrera-Carrillo
Viruses 2023, 15(3), 686; https://0-doi-org.brum.beds.ac.uk/10.3390/v15030686 - 06 Mar 2023
Cited by 2 | Viewed by 2345
Abstract
The current SARS-CoV-2 pandemic forms a major global health burden. Although protective vaccines are available, concerns remain as new virus variants continue to appear. CRISPR-based gene-editing approaches offer an attractive therapeutic strategy as the CRISPR-RNA (crRNA) can be adjusted rapidly to accommodate a [...] Read more.
The current SARS-CoV-2 pandemic forms a major global health burden. Although protective vaccines are available, concerns remain as new virus variants continue to appear. CRISPR-based gene-editing approaches offer an attractive therapeutic strategy as the CRISPR-RNA (crRNA) can be adjusted rapidly to accommodate a new viral genome sequence. This study aimed at using the RNA-targeting CRISPR-Cas13d system to attack highly conserved sequences in the viral RNA genome, thereby preparing for future zoonotic outbreaks of other coronaviruses. We designed 29 crRNAs targeting highly conserved sequences along the complete SARS-CoV-2 genome. Several crRNAs demonstrated efficient silencing of a reporter with the matching viral target sequence and efficient inhibition of a SARS-CoV-2 replicon. The crRNAs that suppress SARS-CoV-2 were also able to suppress SARS-CoV, thus demonstrating the breadth of this antiviral strategy. Strikingly, we observed that only crRNAs directed against the plus-genomic RNA demonstrated antiviral activity in the replicon assay, in contrast to those that bind the minus-genomic RNA, the replication intermediate. These results point to a major difference in the vulnerability and biology of the +RNA versus −RNA strands of the SARS-CoV-2 genome and provide important insights for the design of RNA-targeting antivirals. Full article
(This article belongs to the Special Issue Advances in Antiviral Agents against SARS-CoV-2 and Its Variants)
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Review

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22 pages, 3127 KiB  
Review
Recent Developments and Future Perspectives of Vaccines and Therapeutic Agents against SARS-CoV2 Using the BCOV_S1_CTD of the S Protein
by Amit Gupta, Ashish P. Singh, Vinay K. Singh and Rajeshwar P. Sinha
Viruses 2023, 15(6), 1234; https://0-doi-org.brum.beds.ac.uk/10.3390/v15061234 - 24 May 2023
Cited by 2 | Viewed by 1475
Abstract
Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, the virus kept developing and mutating into different variants over time, which also gained increased transmissibility and spread in populations at a higher pace, culminating in successive waves of COVID-19 cases. The scientific [...] Read more.
Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, the virus kept developing and mutating into different variants over time, which also gained increased transmissibility and spread in populations at a higher pace, culminating in successive waves of COVID-19 cases. The scientific community has developed vaccines and antiviral agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease. Realizing that growing SARS-CoV-2 variations significantly impact the efficacy of antiviral therapies and vaccines, we summarize the appearance and attributes of SARS-CoV-2 variants for future perspectives in drug design, providing up-to-date insights for developing therapeutic agents targeting the variants. The Omicron variant is among the most mutated form; its strong transmissibility and immune resistance capacity have prompted international worry. Most mutation sites currently being studied are in the BCOV_S1_CTD of the S protein. Despite this, several hurdles remain, such as developing vaccination and pharmacological treatment efficacies for emerging mutants of SARS-CoV-2 strains. In this review, we present an updated viewpoint on the current issues faced by the emergence of various SARS-CoV-2 variants. Furthermore, we discuss the clinical studies conducted to assist the development and dissemination of vaccines, small molecule therapeutics, and therapeutic antibodies having broad-spectrum action against SARS-CoV-2 strains. Full article
(This article belongs to the Special Issue Advances in Antiviral Agents against SARS-CoV-2 and Its Variants)
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22 pages, 677 KiB  
Review
Remdesivir Use in the Real-World Setting: An Overview of Available Evidence
by Karolina Akinosoglou, Emmanouil Angelos Rigopoulos, Georgios Schinas, Georgia Kaiafa, Eleni Polyzou, Stamatia Tsoupra, Argyrios Tzouvelekis, Charalambos Gogos and Christos Savopoulos
Viruses 2023, 15(5), 1167; https://0-doi-org.brum.beds.ac.uk/10.3390/v15051167 - 14 May 2023
Cited by 3 | Viewed by 2011
Abstract
In the years of Coronavirus Disease 2019 (COVID-19), various treatment options have been utilized. COVID-19 continues to circulate in the global population, and the evolution of the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has posed significant challenges to the treatment and [...] Read more.
In the years of Coronavirus Disease 2019 (COVID-19), various treatment options have been utilized. COVID-19 continues to circulate in the global population, and the evolution of the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has posed significant challenges to the treatment and prevention of infection. Remdesivir (RDV), an anti-viral agent with in vitro efficacy against coronaviruses, is a potent and safe treatment as suggested by a plethora of in vitro and in vivo studies and clinical trials. Emerging real-world data have confirmed its effectiveness, and there are currently datasets evaluating its efficacy and safety against SARS-CoV-2 infections in various clinical scenarios, including some that are not in the SmPC recommendations according for COVID-19 pharmacotherapy. Remdesivir increases the chance of recovery, reduces progression to severe disease, lowers mortality rates, and exhibits beneficial post-hospitalization outcomes, especially when used early in the course of the disease. Strong evidence suggests the expansion of remdesivir use in special populations (e.g., pregnancy, immunosuppression, renal impairment, transplantation, elderly and co-medicated patients) where the benefits of treatment outweigh the risk of adverse effects. In this article, we attempt to overview the available real-world data of remdesivir pharmacotherapy. With the unpredictable course of COVID-19, we need to utilize all available knowledge to bridge the gap between clinical research and clinical practice and be sufficiently prepared for the future. Full article
(This article belongs to the Special Issue Advances in Antiviral Agents against SARS-CoV-2 and Its Variants)
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19 pages, 1640 KiB  
Review
Mechanistic-Based Classification of Endocytosis-Related Inhibitors: Does It Aid in Assigning Drugs against SARS-CoV-2?
by Mohamed Hessien, Thoria Donia, Ashraf A. Tabll, Eiman Adly, Tawfeek H. Abdelhafez, Amany Attia, Samar Sami Alkafaas, Lucija Kuna, Marija Glasnovic, Vesna Cosic, Robert Smolic and Martina Smolic
Viruses 2023, 15(5), 1040; https://0-doi-org.brum.beds.ac.uk/10.3390/v15051040 - 23 Apr 2023
Cited by 4 | Viewed by 2062
Abstract
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) canonically utilizes clathrin-mediated endocytosis (CME) and several other endocytic mechanisms to invade airway epithelial cells. Endocytic inhibitors, particularly those targeting CME-related proteins, have been identified as promising antiviral drugs. Currently, these inhibitors are ambiguously classified as chemical, [...] Read more.
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) canonically utilizes clathrin-mediated endocytosis (CME) and several other endocytic mechanisms to invade airway epithelial cells. Endocytic inhibitors, particularly those targeting CME-related proteins, have been identified as promising antiviral drugs. Currently, these inhibitors are ambiguously classified as chemical, pharmaceutical, or natural inhibitors. However, their varying mechanisms may suggest a more realistic classification system. Herein, we present a new mechanistic-based classification of endocytosis inhibitors, in which they are segregated among four distinct classes including: (i) inhibitors that disrupt endocytosis-related protein–protein interactions, and assembly or dissociation of complexes; (ii) inhibitors of large dynamin GTPase and/or kinase/phosphatase activities associated with endocytosis; (iii) inhibitors that modulate the structure of subcellular components, especially the plasma membrane, and actin; and (iv) inhibitors that cause physiological or metabolic alterations in the endocytosis niche. Excluding antiviral drugs designed to halt SARS-CoV-2 replication, other drugs, either FDA-approved or suggested through basic research, could be systematically assigned to one of these classes. We observed that many anti-SARS-CoV-2 drugs could be included either in class III or IV as they interfere with the structural or physiological integrity of subcellular components, respectively. This perspective may contribute to our understanding of the relative efficacy of endocytosis-related inhibitors and support the optimization of their individual or combined antiviral potential against SARS-CoV-2. However, their selectivity, combined effects, and possible interactions with non-endocytic cellular targets need more clarification. Full article
(This article belongs to the Special Issue Advances in Antiviral Agents against SARS-CoV-2 and Its Variants)
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14 pages, 1773 KiB  
Review
Nonthermal Biocompatible Plasma Inactivation of Coronavirus SARS-CoV-2: Prospects for Future Antiviral Applications
by Ihn Han, Sohail Mumtaz and Eun Ha Choi
Viruses 2022, 14(12), 2685; https://0-doi-org.brum.beds.ac.uk/10.3390/v14122685 - 30 Nov 2022
Cited by 9 | Viewed by 2420
Abstract
The coronavirus disease (COVID-19) pandemic has placed a massive impact on global civilization. Finding effective treatments and drugs for these viral diseases was crucial. This paper outlined and highlighted key elements of recent advances in nonthermal biocompatible plasma (NBP) technology for antiviral applications. [...] Read more.
The coronavirus disease (COVID-19) pandemic has placed a massive impact on global civilization. Finding effective treatments and drugs for these viral diseases was crucial. This paper outlined and highlighted key elements of recent advances in nonthermal biocompatible plasma (NBP) technology for antiviral applications. We searched for papers on NBP virus inactivation in PubMed ePubs, Scopus, and Web of Science databases. The data and relevant information were gathered in order to establish a mechanism for NBP-based viral inactivation. NBP has been developed as a new, effective, and safe strategy for viral inactivation. NBP may be used to inactivate viruses in an ecologically friendly way as well as activate animal and plant viruses in a number of matrices. The reactive species have been shown to be the cause of viral inactivation. NBP-based disinfection techniques provide an interesting solution to many of the problems since they are simply deployable and do not require the resource-constrained consumables and reagents required for traditional decontamination treatments. Scientists are developing NBP technology solutions to assist the medical community in dealing with the present COVID-19 outbreak. NBP is predicted to be the most promising strategy for battling COVID-19 and other viruses in the future. Full article
(This article belongs to the Special Issue Advances in Antiviral Agents against SARS-CoV-2 and Its Variants)
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