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Novel Antivirals against Respiratory Viruses

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: 20 September 2024 | Viewed by 14282

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Special Issue Editors

Dr. Fabiana Superti

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Guest Editor

National Centre for Innovative Technologies in Public Health, National Institute of Health, Viale Regina Elena 299, 00161 Rome, Italy
Interests: virus-host cell interaction; virulence factors; viral receptors; viral entry; antiviral drugs; lactoferrin; lipophilic amines; antiviral peptides; natural and synthetic antiviral compounds; Influenza virus; Adenovirus

Dr. Magda Marchetti

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Guest Editor

National Centre for Innovative Technologies in Public Health, National Institute of Health, Viale Regina Elena 299, 00161 Rome, Italy
Interests: natural antiviral compounds; antiviral activity of lactoferrin; cell toxicity; interference with early stages of viral infection; Influenza virus; Adenovirus; Herpesvirus

Dr. Lucia Nencioni

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Guest Editor

Department of Public Health and Infectious Diseases, Microbiology Section, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185 Rome, Italy
Interests: molecular mechanisms involved in regulation of viral replication and host cell response; relationship between intra/extracellular redox state and viral infection and evaluation of antiviral effect of compounds with antioxidant activity in vitro and in vivo models; new antiviral strategies aimed at inhibiting host cell functions; rather than viral structure; that are essential for replication of different viruses; identification and characterization of new synthesized or natural antiviral compounds

Special Issue Information

Dear Colleagues,

Respiratory tract infections are very common in the population and represent a significant cause of high morbidity and mortality worldwide. Viral infections of the upper respiratory tract are mainly caused by rhinoviruses, coronaviruses, influenza viruses, parainfluenza viruses and adenoviruses. Acute viral lower respiratory tract infections, such as SARS-CoV-2, influenza virus, and respiratory syncytial virus infections, represent a significant health problem for both the pediatric and adult populations. In particular, influenza virus and SARS-CoV-2, the cause of epidemics and pandemics, have a very serious impact on human life. Although vaccines and antiviral drugs are available for these viruses, vaccines are not always fully effective against circulating viral strains, and drug resistance poses a significant challenge for treating infections.

Much attention has been paid to research and development of antivirals to fight respiratory infections but the problems of drug resistance and undesirable side effects highlight the need to search for novel and more effective drugs.

In this special issue, we welcome the submission by researchers in the antiviral drug field of original research papers, communications and review articles on one of the following topics:

Identification of cellular and/or viral targets to fight respiratory infections;
Use of natural substances or synthetic molecules to inhibit respiratory virus infections;
Combination of different drugs to fight viral infections of the respiratory tract;
Drug repurposing approaches for the treatment of respiratory viral infections;
Innovative therapies against viral infections of the respiratory tract that combine classic antivirals with host-targeting compounds;
Search for new antivirals that target different steps of viral life cycle.

Dr. Fabiana Superti
Dr. Magda Marchetti
Dr. Lucia Nencioni
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

respiratory virus
antivirals and mechanism of action
antiviral drugs
antiviral drug resistance
antiviral targets
in vitro models
antiviral combination therapy

Published Papers (9 papers)

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Research

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23 pages, 1551 KiB

Open AccessArticle

Amphiphilic Sialic Acid Derivatives as Potential Dual-Specific Inhibitors of Influenza Hemagglutinin and Neuraminidase

by Eszter Boglárka Lőrincz, Mihály Herczeg, Josef Houser, Martina Rievajová, Ákos Kuki, Lenka Malinovská, Lieve Naesens, Michaela Wimmerová, Anikó Borbás, Pál Herczegh and Ilona Bereczki

Int. J. Mol. Sci. 2023, 24(24), 17268; https://doi.org/10.3390/ijms242417268 - 8 Dec 2023

Viewed by 884

Abstract

In the shadow of SARS-CoV-2, influenza seems to be an innocent virus, although new zoonotic influenza viruses evolved by mutations may lead to severe pandemics. According to WHO, there is an urgent need for better antiviral drugs. Blocking viral hemagglutinin with multivalent N-acetylneuraminic acid derivatives is a promising approach to prevent influenza infection. Moreover, dual inhibition of both hemagglutinin and neuraminidase may result in a more powerful effect. Since both viral glycoproteins can bind to neuraminic acid, we have prepared three series of amphiphilic self-assembling 2-thio-neuraminic acid derivatives constituting aggregates in aqueous medium to take advantage of their multivalent effect. One of the series was prepared by the azide-alkyne click reaction, and the other two by the thio-click reaction to yield neuraminic acid derivatives containing lipophilic tails of different sizes and an enzymatically stable thioglycosidic bond. Two of the three bis-octyl derivatives produced proved to be active against influenza viruses, while all three octyl derivatives bound to hemagglutinin and neuraminidase from H1N1 and H3N2 influenza types. Full article

(This article belongs to the Special Issue Novel Antivirals against Respiratory Viruses)

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17 pages, 3183 KiB

Open AccessArticle

Rational Design of Novel Peptidomimetics against Influenza A Virus: Biological and Computational Studies

by Maria Carmina Scala, Magda Marchetti, Fabiana Superti, Mariangela Agamennone, Pietro Campiglia and Marina Sala

Int. J. Mol. Sci. 2023, 24(18), 14268; https://doi.org/10.3390/ijms241814268 - 19 Sep 2023

Cited by 2 | Viewed by 987

Abstract

Effective therapy against the influenza virus is still an unmet goal. Drugs with antiviral effects exist, but the appearance of resistant viruses pushes towards the discovery of drugs with different mechanisms of action. New anti-influenza molecules should target a good candidate, as a new anti-influenza molecule could be an inhibitor of the influenza A virus hemagglutinin (HA), which plays a key role during the early phases of infection. In previous work, we identified two tetrapeptide sequences, SLDC (1) and SKHS (2), derived from bovine lactoferrin (bLf) C-lobe fragment 418–429, which were able to bind HA and inhibit cell infection at picomolar concentration. Considering the above, the aim of this study was to synthesize a new library of peptidomimetics active against the influenza virus. In order to test their ability to bind HA, we carried out a preliminary screening using biophysical assays such as surface plasmon resonance (SPR) and orthogonal immobilization-free microscale thermophoresis (MST). Biological and computational studies on the most interesting compounds were carried out. The methods applied allowed for the identification of a N-methyl peptide, S(N-Me)LDC, which, through high affinity binding of influenza virus hemagglutinin, was able to inhibit virus-induced hemagglutination and cell infection at picomolar concentration. This small sequence, with high activity, represents a good starting point for the design of new peptidomimetics and small molecules. Full article

(This article belongs to the Special Issue Novel Antivirals against Respiratory Viruses)

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14 pages, 2021 KiB

Open AccessArticle

Hylin-a1: A Pan-Inhibitor against Emerging and Re-Emerging Respiratory Viruses

by Annalisa Chianese, Carla Zannella, Alessandra Monti, Nunzianna Doti, Giuseppina Sanna, Aldo Manzin, Anna De Filippis and Massimiliano Galdiero

Int. J. Mol. Sci. 2023, 24(18), 13888; https://doi.org/10.3390/ijms241813888 - 9 Sep 2023

Cited by 1 | Viewed by 1072

Abstract

Pandemic and epidemic outbreaks of respiratory viruses are a challenge for public health and social care system worldwide, leading to high mortality and morbidity among the human populations. In light of the limited efficacy of current vaccines and antiviral drugs against respiratory viral infections and the emergence and re-emergence of new viruses, novel broad-spectrum antiviral drugs are needed for the prevention and treatment of these infections. Antimicrobial peptides with an antiviral effect, also known as AVPs, have already been reported as potent inhibitors of viral infections by affecting different stages of the virus lifecycle. In the present study, we analyzed the activity of the AVP Hylin-a1, secreted by the frog Hypsiboas albopunctatus, against a wide range of respiratory viruses, including the coronaviruses HCoV-229E and SARS-CoV-2, measles virus, human parainfluenza virus type 3, and influenza virus H1N1. We report a significant inhibitory effect on infectivity in all the enveloped viruses, whereas there was a lack of activity against the naked coxsackievirus B3. Considering the enormous therapeutic potential of Hylin-a1, further experiments are required to elucidate its mechanism of action and to increase its stability by modifying the native sequence. Full article

(This article belongs to the Special Issue Novel Antivirals against Respiratory Viruses)

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18 pages, 4266 KiB

Open AccessArticle

Identification of Anti-Influenza A Compounds Inhibiting the Viral Non-Structural Protein 1 (NS1) Using a Type I Interferon-Driven Screening Strategy

by Giulia Marsili, Chiara Acchioni, Anna Lisa Remoli, Donatella Amatore, Rossella Sgarbanti, Marta De Angelis, Roberto Orsatti, Marta Acchioni, Andrea Astolfi, Nunzio Iraci, Simona Puzelli, Marzia Facchini, Edvige Perrotti, Violetta Cecchetti, Stefano Sabatini, Fabiana Superti, Mariangela Agamennone, Maria Letizia Barreca, John Hiscott, Lucia Nencioni and Marco Sgarbanti Show full author list Hide full author list

Int. J. Mol. Sci. 2023, 24(13), 10495; https://doi.org/10.3390/ijms241310495 - 22 Jun 2023

Cited by 2 | Viewed by 1399

Abstract

There is an urgent need to identify efficient antiviral compounds to combat existing and emerging RNA virus infections, particularly those related to seasonal and pandemic influenza outbreaks. While inhibitors of the influenza viral integral membrane proton channel protein (M2), neuraminidase (NA), and cap-dependent endonuclease are available, circulating influenza viruses acquire resistance over time. Thus, the need for the development of additional anti-influenza drugs with novel mechanisms of action exists. In the present study, a cell-based screening assay and a small molecule library were used to screen for activities that antagonized influenza A non-structural protein 1 (NS1), a highly conserved, multifunctional accessory protein that inhibits the type I interferon response against influenza. Two potential anti-influenza agents, compounds 157 and 164, were identified with anti-NS1 activity, resulting in the reduction of A/PR/8/34(H1N1) influenza A virus replication and the restoration of IFN-β expression in human lung epithelial A549 cells. A 3D pharmacophore modeling study of the active compounds provided a glimpse of the structural motifs that may contribute to anti-influenza virus activity. This screening approach is amenable to a broader analysis of small molecule compounds to inhibit other viral targets. Full article

(This article belongs to the Special Issue Novel Antivirals against Respiratory Viruses)

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10 pages, 1826 KiB

Open AccessArticle

Evaluation of the Antiviral Efficacy of Subcutaneous Nafamostat Formulated with Glycyrrhizic Acid against SARS-CoV-2 in a Murine Model

by Ju Hwan Jeong, Woong Hee Lee, Seong Cheol Min, Beom Kyu Kim, On Bi Park, Santosh Chokkakula, Seong Ju Ahn, Sol Oh, Ji-Hyun Park, Ji Won Jung, Ji Min Jung, Eung-Gook Kim and Min-Suk Song

Int. J. Mol. Sci. 2023, 24(11), 9579; https://doi.org/10.3390/ijms24119579 - 31 May 2023

Cited by 1 | Viewed by 1134

Abstract

The ongoing COVID-19 pandemic highlights the urgent need for effective antiviral agents and vaccines. Drug repositioning, which involves modifying existing drugs, offers a promising approach for expediting the development of novel therapeutics. In this study, we developed a new drug, MDB-MDB-601a-NM, by modifying the existing drug nafamostat (NM) with the incorporation of glycyrrhizic acid (GA). We assessed the pharmacokinetic profiles of MDB-601a-NM and nafamostat in Sprague-Dawley rats, revealing rapid clearance of nafamostat and sustained drug concentration of MDB-601a-NM after subcutaneous administration. Single-dose toxicity studies showed potential toxicity and persistent swelling at the injection site with high-dose administration of MDB-601a-NM. Furthermore, we evaluated the efficacy of MDB-601a-NM in protecting against SARS-CoV-2 infection using the K18 hACE-2 transgenic mouse model. Mice treated with 60 mg/kg and 100 mg/kg of MDB-601a-NM exhibited improved protectivity in terms of weight loss and survival rates compared to the nafamostat-treated group. Histopathological analysis revealed dose-dependent improvements in histopathological changes and enhanced inhibitory efficacy in MDB-601a-NM-treated groups. Notably, no viral replication was detected in the brain tissue when mice were treated with 60 mg/kg and 100 mg/kg of MDB-601a-NM. Our developed MDB-601a-NM, a modified Nafamostat with glycyrrhizic acid, shows improved protectivity against SARS-CoV-2 infection. Its sustained drug concentration after subcutaneous administration and dose-dependent improvements makes it a promising therapeutic option. Full article

(This article belongs to the Special Issue Novel Antivirals against Respiratory Viruses)

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19 pages, 6068 KiB

Open AccessArticle

In Vitro Antiviral and Anti-Inflammatory Activities of N-Acetylglucosamine: Development of an Alternative and Safe Approach to Fight Viral Respiratory Infections

by Magda Marchetti, Barbara De Berardis, Irene Bigioni, Alessia Mariano, Fabiana Superti and Anna Scotto d’Abusco

Int. J. Mol. Sci. 2023, 24(6), 5129; https://doi.org/10.3390/ijms24065129 - 7 Mar 2023

Cited by 3 | Viewed by 1911

Abstract

Viral respiratory tract infections (RTIs) are responsible for significant morbidity and mortality worldwide. A prominent feature of severe respiratory infections, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is the cytokine release syndrome. Therefore, there is an urgent need to develop different approaches both against viral replication and against the consequent inflammation. N-acetylglucosamine (GlcNAc), a glucosamine (GlcN) derivative, has been developed as an immunomodulatory and anti-inflammatory inexpensive and non-toxic drug for non-communicable disease treatment and/or prevention. Recent studies have suggested that GlcN, due to its anti-inflammatory activity, could be potentially useful for the control of respiratory virus infections. Our present study aimed to evaluate in two different immortalized cell lines whether GlcNAc could inhibit or reduce both viral infectivity and the inflammatory response to viral infection. Two different viruses, frequent cause of upper and lower respiratory tract infections, were used: the H1N1 Influenza A virus (IAV) (as model of enveloped RNA virus) and the Human adenovirus type 2 (Adv) (as model of naked DNA virus). Two forms of GlcNAc have been considered, bulk GlcNAc and GlcNAc in nanoform to overcome the possible pharmacokinetic limitations of GlcNAc. Our study suggests that GlcNAc restricts IAV replication but not Adv infection, whereas nano-GlcNAc inhibits both viruses. Moreover, GlcNAc and mainly its nanoformulation were able to reduce the pro-inflammatory cytokine secretion stimulated by viral infection. The correlation between inflammatory and infection inhibition is discussed. Full article

(This article belongs to the Special Issue Novel Antivirals against Respiratory Viruses)

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16 pages, 2076 KiB

Open AccessArticle

Discovery and Optimization of Neutralizing SARS-CoV-2 Antibodies Using ALTHEA Gold Plus Libraries™

by Omar U. Guzmán-Bringas, Keyla M. Gómez-Castellano, Edith González-González, Juana Salinas-Trujano, Said Vázquez-Leyva, Luis Vallejo-Castillo, Sonia M. Pérez-Tapia and Juan C. Almagro

Int. J. Mol. Sci. 2023, 24(5), 4609; https://doi.org/10.3390/ijms24054609 - 27 Feb 2023

Viewed by 1821

Abstract

We recently reported the isolation and characterization of anti-SARS-CoV-2 antibodies from a phage display library built with the VH repertoire of a convalescent COVID-19 patient, paired with four naïve synthetic VL libraries. One of the antibodies, called IgG-A7, neutralized the Wuhan, Delta (B.1.617.2) and Omicron (B.1.1.529) strains in authentic neutralization tests (PRNT). It also protected 100% transgenic mice expressing the human angiotensin-converting enzyme 2 (hACE-2) from SARS-CoV-2 infection. In this study, the four synthetic VL libraries were combined with the semi-synthetic VH repertoire of ALTHEA Gold Libraries™ to generate a set of fully naïve, general-purpose, libraries called ALTHEA Gold Plus Libraries™. Three out of 24 specific clones for the RBD isolated from the libraries, with affinity in the low nanomolar range and sub-optimal in vitro neutralization in PRNT, were affinity optimized via a method called “Rapid Affinity Maturation” (RAM). The final molecules reached sub-nanomolar neutralization potency, slightly superior to IgG-A7, while the developability profile over the parental molecules was improved. These results demonstrate that general-purpose libraries are a valuable source of potent neutralizing antibodies. Importantly, since general-purpose libraries are “ready-to-use”, it could expedite isolation of antibodies for rapidly evolving viruses such as SARS-CoV-2. Full article

(This article belongs to the Special Issue Novel Antivirals against Respiratory Viruses)

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Review

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16 pages, 338 KiB

Open AccessReview

Small Molecules Targeting Viral RNA

by Gregory Mathez and Valeria Cagno

Int. J. Mol. Sci. 2023, 24(17), 13500; https://doi.org/10.3390/ijms241713500 - 31 Aug 2023

Cited by 2 | Viewed by 1608

Abstract

The majority of antivirals available target viral proteins; however, RNA is emerging as a new and promising antiviral target due to the presence of highly structured RNA in viral genomes fundamental for their replication cycle. Here, we discuss methods for the identification of RNA-targeting compounds, starting from the determination of RNA structures either from purified RNA or in living cells, followed by in silico screening on RNA and phenotypic assays to evaluate viral inhibition. Moreover, we review the small molecules known to target the programmed ribosomal frameshifting element of SARS-CoV-2, the internal ribosomal entry site of different viruses, and RNA elements of HIV. Full article

(This article belongs to the Special Issue Novel Antivirals against Respiratory Viruses)

33 pages, 3529 KiB

Open AccessReview

Aprotinin—Drug against Respiratory Diseases

by Alexandre V. Ivachtchenko, Andrey A. Ivashchenko, Dmitrii O. Shkil and Ilya A. Ivashchenko

Int. J. Mol. Sci. 2023, 24(13), 11173; https://doi.org/10.3390/ijms241311173 - 6 Jul 2023

Cited by 3 | Viewed by 2195

Abstract

Aprotinin (APR) was discovered in 1930. APR is an effective pan-protease inhibitor, a typical “magic shotgun”. Until 2007, APR was widely used as an antithrombotic and anti-inflammatory drug in cardiac and noncardiac surgeries for reduction of bleeding and thus limiting the need for blood transfusion. The ability of APR to inhibit proteolytic activation of some viruses leads to its use as an antiviral drug for the prevention and treatment of acute respiratory virus infections. However, due to incompetent interpretation of several clinical trials followed by incredible controversy in the literature, the usage of APR was nearly stopped for a decade worldwide. In 2015–2020, after re-analysis of these clinical trials’ data the restrictions in APR usage were lifted worldwide. This review discusses antiviral mechanisms of APR action and summarizes current knowledge and prospective regarding the use of APR treatment for diseases caused by RNA-containing viruses, including influenza and SARS-CoV-2 viruses, or as a part of combination antiviral treatment. Full article

(This article belongs to the Special Issue Novel Antivirals against Respiratory Viruses)

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