International Journal of Molecular Sciences

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5 pages, 223 KiB

Open AccessEditorial

Antivirals and Vaccines

by Nuno Taveira

Int. J. Mol. Sci. 2023, 24(12), 10315; https://doi.org/10.3390/ijms241210315 - 19 Jun 2023

Viewed by 1906

Abstract

New antivirals are urgently needed to treat respiratory diseases caused by RNA viruses [...] Full article

(This article belongs to the Special Issue Antivirals and Vaccines)

Research

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14 pages, 2398 KiB

Open AccessArticle

R-Propranolol Has Broad-Spectrum Anti-Coronavirus Activity and Suppresses Factors Involved in Pathogenic Angiogenesis

by Melissa Thaler, Clarisse Salgado-Benvindo, Anouk Leijs, Ali Tas, Dennis K. Ninaber, Jack L. Arbiser, Eric J. Snijder and Martijn J. van Hemert

Int. J. Mol. Sci. 2023, 24(5), 4588; https://doi.org/10.3390/ijms24054588 - 27 Feb 2023

Cited by 4 | Viewed by 2355

Abstract

The SARS-CoV-2 pandemic highlighted the need for broad-spectrum antivirals to increase our preparedness. Patients often require treatment by the time that blocking virus replication is less effective. Therefore, therapy should not only aim to inhibit the virus, but also to suppress pathogenic host [...] Read more.

The SARS-CoV-2 pandemic highlighted the need for broad-spectrum antivirals to increase our preparedness. Patients often require treatment by the time that blocking virus replication is less effective. Therefore, therapy should not only aim to inhibit the virus, but also to suppress pathogenic host responses, e.g., leading to microvascular changes and pulmonary damage. Clinical studies have previously linked SARS-CoV-2 infection to pathogenic intussusceptive angiogenesis in the lungs, involving the upregulation of angiogenic factors such as ANGPTL4. The β-blocker propranolol is used to suppress aberrant ANGPTL4 expression in the treatment of hemangiomas. Therefore, we investigated the effect of propranolol on SARS-CoV-2 infection and the expression of ANGPTL4. SARS-CoV-2 upregulated ANGPTL4 in endothelial and other cells, which could be suppressed with R-propranolol. The compound also inhibited the replication of SARS-CoV-2 in Vero-E6 cells and reduced the viral load by up to ~2 logs in various cell lines and primary human airway epithelial cultures. R-propranolol was as effective as S-propranolol but lacks the latter’s undesired β-blocker activity. R-propranolol also inhibited SARS-CoV and MERS-CoV. It inhibited a post-entry step of the replication cycle, likely via host factors. The broad-spectrum antiviral effect and suppression of factors involved in pathogenic angiogenesis make R-propranolol an interesting molecule to further explore for the treatment of coronavirus infections. Full article

(This article belongs to the Special Issue Antivirals and Vaccines)

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15 pages, 5362 KiB

Open AccessArticle

A Recombinant Genotype I Japanese Encephalitis Virus Expressing a Gaussia Luciferase Gene for Antiviral Drug Screening Assay and Neutralizing Antibodies Detection

by Chenxi Li, Xuan Chen, Jingbo Hu, Daoyuan Jiang, Demin Cai and Yanhua Li

Int. J. Mol. Sci. 2022, 23(24), 15548; https://doi.org/10.3390/ijms232415548 - 8 Dec 2022

Cited by 4 | Viewed by 1786

Abstract

Japanese encephalitis virus (JEV) is the major cause of viral encephalitis in humans throughout Asia. In the past twenty years, the emergence of the genotype I (GI) JEV as the dominant genotype in Asian countries has raised a significant threat to public health [...] Read more.

Japanese encephalitis virus (JEV) is the major cause of viral encephalitis in humans throughout Asia. In the past twenty years, the emergence of the genotype I (GI) JEV as the dominant genotype in Asian countries has raised a significant threat to public health security. However, no clinically approved drug is available for the specific treatment of JEV infection, and the commercial vaccines derived from the genotype III JEV strains merely provided partial protection against the GI JEV. Thus, an easy-to-perform platform in high-throughput is urgently needed for the antiviral drug screening and assessment of neutralizing antibodies specific against the GI JEV. In this study, we established a reverse genetics system for the GI JEV strain (YZ-1) using a homologous recombination strategy. Using this reverse genetic system, a gaussia luciferase (Gluc) expression cassette was inserted into the JEV genome to generate a reporter virus (rGI-Gluc). The reporter virus exhibited similar growth kinetics to the parental virus and remained genetically stable for at least ten passages in vitro. Of note, the bioluminescence signal strength of Gluc in the culture supernatants was well correlated with the viral progenies determined by viral titration. Taking advantage of this reporter virus, we established Gluc readout-based assays for antiviral drug screening and neutralizing antibody detection against the GI JEV. These Gluc readout-based assays exhibited comparable performance to the assays using an actual virus and are less time consuming and are applicable for a high-throughput format. Taken together, we generated a GI JEV reporter virus expressing a Gluc gene that could be a valuable tool for an antiviral drug screening assay and neutralization assay. Full article

(This article belongs to the Special Issue Antivirals and Vaccines)

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15 pages, 3636 KiB

Open AccessArticle

2’-Fucosyllactose Inhibits Coxsackievirus Class A Type 9 Infection by Blocking Virus Attachment and Internalisation

by Fuxing Lou, Ruolan Hu, Yangzhen Chen, Mengzhe Li, Xiaoping An, Lihua Song, Yigang Tong and Huahao Fan

Int. J. Mol. Sci. 2022, 23(22), 13727; https://doi.org/10.3390/ijms232213727 - 8 Nov 2022

Cited by 3 | Viewed by 1767

Abstract

Coxsackieviruses, a genus of enteroviruses in the small RNA virus family, cause fatal infectious diseases in humans. Thus far, there are no approved drugs to prevent these diseases. Human milk contains various biologically active components against pathogens. Currently, the potential activity of breast [...] Read more.

Coxsackieviruses, a genus of enteroviruses in the small RNA virus family, cause fatal infectious diseases in humans. Thus far, there are no approved drugs to prevent these diseases. Human milk contains various biologically active components against pathogens. Currently, the potential activity of breast milk components against the coxsackievirus remains unclear. In our study, the inhibitory effect of 16 major human milk components was tested on coxsackievirus class A type 9 isolate (CV-A9), BUCT01; 2’-Fucosyllactose (2’-FL) was identified to be effective. Time-of-addition, attachment internalisation assays, and the addition of 2’-FL at different time points were applied to investigate its specific role in the viral life cycle. Molecular docking was used to predict 2’-FL’s specific cellular targets. The initial screening revealed a significant inhibitory effect (99.97%) against CV-A9 with 10 mg/mL 2’-FL, with no cytotoxicity observed. Compared with the control group, 2’-FL blocked virus entry (85%) as well as inhibited viral attachment (48.4%) and internalisation (51.3%), minimising its infection in rhabdomyosarcoma (RD) cells. The cell pre-incubation with 2’-FL exhibited significant inhibition (73.2–99.9%). Extended incubation between cells with 2’-FL reduced CV-A9 infection (93.9%), suggesting that 2’-FL predominantly targets cells to block infection. Molecular docking results revealed that 2’-FL interacted with the attachment receptor α_vβ₆ and the internalisation receptor FCGRT and β₂M with an affinity of −2.14, −1.87, and −5.43 kcal/mol, respectively. This study lays the foundation for using 2’-FL as a food additive against CV-A9 infections. Full article

(This article belongs to the Special Issue Antivirals and Vaccines)

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16 pages, 4169 KiB

Open AccessArticle

Antiviral Drugs Screening for Swine Acute Diarrhea Syndrome Coronavirus

by Yangzhen Chen, Yecheng You, Shuqi Wang, Lin Jiang, Lili Tian, Shaozhou Zhu, Xiaoping An, Lihua Song, Yigang Tong and Huahao Fan

Int. J. Mol. Sci. 2022, 23(19), 11250; https://doi.org/10.3390/ijms231911250 - 24 Sep 2022

Cited by 9 | Viewed by 2332

Abstract

Coronaviruses as possible cross-species viruses have caused several epidemics. The ongoing emergency of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has posed severe threats to the global economy and public health, which has generated great concerns about zoonotic viruses. Swine acute diarrhea syndrome [...] Read more.

Coronaviruses as possible cross-species viruses have caused several epidemics. The ongoing emergency of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has posed severe threats to the global economy and public health, which has generated great concerns about zoonotic viruses. Swine acute diarrhea syndrome coronavirus (SADS-CoV), an alpha-coronavirus, was responsible for mass piglet deaths, resulting in unprecedented economic losses, and no approved drugs or vaccines are currently available for SADS-CoV infection. Given its potential ability to cause cross-species infection, it is essential to develop specific antiviral drugs and vaccines against SADS-CoV. Drug screening was performed on a total of 3523 compound-containing drug libraries as a strategy of existing medications repurposing. We identified five compounds (gemcitabine, mycophenolate mofetil, mycophenolic acid, methylene blue and cepharanthine) exhibiting inhibitory effects against SADS-CoV in a dose-dependent manner. Cepharanthine and methylene blue were confirmed to block viral entry, and gemcitabine, mycophenolate mofetil, mycophenolic acid and methylene blue could inhibit viral replication after SADS-CoV entry. This is the first report on SADS-CoV drug screening, and we found five compounds from drug libraries to be potential anti-SADS-CoV drugs, supporting the development of antiviral drugs for a possible outbreak of SADS-CoV in the future. Full article

(This article belongs to the Special Issue Antivirals and Vaccines)

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18 pages, 6400 KiB

Open AccessArticle

Synergistic Antiviral Activity of Pamapimod and Pioglitazone against SARS-CoV-2 and Its Variants of Concern

by Christian Setz, Maximilian Große, Janina Auth, Maria Fröba, Pia Rauch, Alexander Bausch, Matthew Wright and Ulrich Schubert

Int. J. Mol. Sci. 2022, 23(12), 6830; https://doi.org/10.3390/ijms23126830 - 20 Jun 2022

Cited by 8 | Viewed by 3810

Abstract

The SARS-CoV-2 pandemic remains a major public health threat, especially due to newly emerging SARS-CoV-2 Variants of Concern (VoCs), which are more efficiently transmitted, more virulent, and more able to escape naturally acquired and vaccine-induced immunity. Recently, the protease inhibitor Paxlovid^® and [...] Read more.

The SARS-CoV-2 pandemic remains a major public health threat, especially due to newly emerging SARS-CoV-2 Variants of Concern (VoCs), which are more efficiently transmitted, more virulent, and more able to escape naturally acquired and vaccine-induced immunity. Recently, the protease inhibitor Paxlovid^® and the polymerase inhibitor molnupiravir, both targeting mutant-prone viral components, were approved for high-risk COVID-19 patients. Nevertheless, effective therapeutics to treat COVID-19 are urgently needed, especially small molecules acting independently of VoCs and targeting genetically stable cellular pathways which are crucial for viral replication. Pamapimod is a selective inhibitor of p38 Mitogen-Activated Protein Kinase alpha (p38 MAPKα) that has been extensively clinically evaluated for the treatment of rheumatoid arthritis. Signaling via p38 has recently been described as a key pathway for the replication of SARS-CoV-2. Here, we reveal that the combination of pamapimod with pioglitazone, an anti-inflammatory and approved drug for the treatment of type 2 diabetes, possesses potent and synergistic activity to inhibit SARS-CoV-2 replication in vitro. Both drugs showed similar antiviral potency across several cultured cell types and similar antiviral activity against SARS-CoV-2 Wuhan type, and the VoCs Alpha, Beta, Gamma, Delta, and Omicron. These data support the combination of pamapimod and pioglitazone as a potential therapy to reduce duration and severity of disease in COVID-19 patients, an assumption currently evaluated in an ongoing phase II clinical study. Full article

(This article belongs to the Special Issue Antivirals and Vaccines)

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14 pages, 2573 KiB

Open AccessArticle

Development of Viral-Vectored Vaccines and Virus Replicon Particle-Based Neutralisation Assay against Mayaro Virus

by Young Chan Kim, Arlen-Celina Lücke, César López-Camacho, Beate Mareike Kümmerer and Arturo Reyes-Sandoval

Int. J. Mol. Sci. 2022, 23(8), 4105; https://doi.org/10.3390/ijms23084105 - 7 Apr 2022

Cited by 5 | Viewed by 2367

Abstract

Mayaro virus (MAYV) is an emerging alphavirus causing acute febrile illness associated with chronic polyarthralgia. Although MAYV is currently restricted to tropical regions in South America around the Amazon basin, it has the potential to spread globally by Aedes species mosquitoes. In addition, [...] Read more.

Mayaro virus (MAYV) is an emerging alphavirus causing acute febrile illness associated with chronic polyarthralgia. Although MAYV is currently restricted to tropical regions in South America around the Amazon basin, it has the potential to spread globally by Aedes species mosquitoes. In addition, there are currently no specific therapeutics or licenced vaccines against MAYV infection. We have previously shown that an adenovirus based Mayaro vaccine (ChAdOx1 May) was able to provide full protection against MAYV challenge in vaccinated A129 mice and induced high neutralising antibody titres. In this study, we have constructed a replication deficient simian adenovirus (ChAdOx2) and a Modified Ankara Virus (MVA) based vaccine expressing the MAYV structural cassette (sMAYV) similar to ChAdOx1 May, and characterised recombinant MAYV E2 glycoprotein expressed in a mammalian system for immune monitoring. We demonstrate that ChAdOx2 May was able to induce high antibody titres similar to ChAdOx1 May, and MVA May was shown to be an effective boosting strategy following prime vaccination with ChAdOx1 or ChAdOx2 May. In order to measure MAYV neutralising ability, we have developed a virus replicon particle-based neutralisation assay which effectively detected neutralising antibodies against MAYV. In summary, our study indicates the potential for further clinical development of the viral vectored MAYV vaccines against MAYV infections. Full article

(This article belongs to the Special Issue Antivirals and Vaccines)

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Review

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19 pages, 743 KiB

Open AccessReview

Antiretroviral Treatment of HIV-2 Infection: Available Drugs, Resistance Pathways, and Promising New Compounds

by Inês Moranguinho, Nuno Taveira and Inês Bártolo

Int. J. Mol. Sci. 2023, 24(6), 5905; https://doi.org/10.3390/ijms24065905 - 21 Mar 2023

Cited by 14 | Viewed by 4361

Abstract

Currently, it is estimated that 1–2 million people worldwide are infected with HIV-2, accounting for 3–5% of the global burden of HIV. The course of HIV-2 infection is longer compared to HIV-1 infection, but without effective antiretroviral therapy (ART), a substantial proportion of [...] Read more.

Currently, it is estimated that 1–2 million people worldwide are infected with HIV-2, accounting for 3–5% of the global burden of HIV. The course of HIV-2 infection is longer compared to HIV-1 infection, but without effective antiretroviral therapy (ART), a substantial proportion of infected patients will progress to AIDS and die. Antiretroviral drugs in clinical use were designed for HIV-1 and, unfortunately, some do not work as well, or do not work at all, for HIV-2. This is the case for non-nucleoside reverse transcriptase inhibitors (NNRTIs), the fusion inhibitor enfuvirtide (T-20), most protease inhibitors (PIs), the attachment inhibitor fostemsavir and most broadly neutralizing antibodies. Integrase inhibitors work well against HIV-2 and are included in first-line therapeutic regimens for HIV-2-infected patients. However, rapid emergence of drug resistance and cross-resistance within each drug class dramatically reduces second-line treatment options. New drugs are needed to treat infection with drug-resistant isolates. Here, we review the therapeutic armamentarium available to treat HIV-2-infected patients, as well as promising drugs in development. We also review HIV-2 drug resistance mutations and resistance pathways that develop in HIV-2-infected patients under treatment. Full article

(This article belongs to the Special Issue Antivirals and Vaccines)

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