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19 pages, 5191 KiB

Open AccessArticle

Photodynamic Inactivation of Human Coronaviruses

by Brett A. Duguay, Adrian Herod, Eric S. Pringle, Susan M. A. Monro, Marc Hetu, Colin G. Cameron, Sherri A. McFarland and Craig McCormick

Viruses 2022, 14(1), 110; https://doi.org/10.3390/v14010110 - 8 Jan 2022

Cited by 15 | Viewed by 3650

Abstract

Photodynamic inactivation (PDI) employs a photosensitizer, light, and oxygen to create a local burst of reactive oxygen species (ROS) that can inactivate microorganisms. The botanical extract PhytoQuin^TM is a powerful photosensitizer with antimicrobial properties. We previously demonstrated that photoactivated PhytoQuin also has [...] Read more.

Photodynamic inactivation (PDI) employs a photosensitizer, light, and oxygen to create a local burst of reactive oxygen species (ROS) that can inactivate microorganisms. The botanical extract PhytoQuin^TM is a powerful photosensitizer with antimicrobial properties. We previously demonstrated that photoactivated PhytoQuin also has antiviral properties against herpes simplex viruses and adenoviruses in a dose-dependent manner across a broad range of sub-cytotoxic concentrations. Here, we report that human coronaviruses (HCoVs) are also susceptible to photodynamic inactivation. Photoactivated-PhytoQuin inhibited the replication of the alphacoronavirus HCoV-229E and the betacoronavirus HCoV-OC43 in cultured cells across a range of sub-cytotoxic doses. This antiviral effect was light-dependent, as we observed minimal antiviral effect of PhytoQuin in the absence of photoactivation. Using RNase protection assays, we observed that PDI disrupted HCoV particle integrity allowing for the digestion of viral RNA by exogenous ribonucleases. Using lentiviruses pseudotyped with the SARS-CoV-2 Spike (S) protein, we once again observed a strong, light-dependent antiviral effect of PhytoQuin, which prevented S-mediated entry into human cells. We also observed that PhytoQuin PDI altered S protein electrophoretic mobility. The PhytoQuin constituent emodin displayed equivalent light-dependent antiviral activity to PhytoQuin in matched-dose experiments, indicating that it plays a central role in PhytoQuin PDI against CoVs. Together, these findings demonstrate that HCoV lipid envelopes and proteins are damaged by PhytoQuin PDI and expands the list of susceptible viruses. Full article

(This article belongs to the Special Issue Antivirals for Newly Emerging Viral Diseases of Global Importance)

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21 pages, 4735 KiB

Open AccessArticle

Enhancing the Antiviral Potency of Nucleobases for Potential Broad-Spectrum Antiviral Therapies

by Ruben Soto-Acosta, Tiffany C. Edwards, Christine D. Dreis, Venkatramana D. Krishna, Maxim C-J. Cheeran, Li Qiu, Jiashu Xie, Laurent F. Bonnac and Robert J. Geraghty

Viruses 2021, 13(12), 2508; https://doi.org/10.3390/v13122508 - 14 Dec 2021

Cited by 1 | Viewed by 3215

Abstract

Broad-spectrum antiviral therapies hold promise as a first-line defense against emerging viruses by blunting illness severity and spread until vaccines and virus-specific antivirals are developed. The nucleobase favipiravir, often discussed as a broad-spectrum inhibitor, was not effective in recent clinical trials involving patients [...] Read more.

Broad-spectrum antiviral therapies hold promise as a first-line defense against emerging viruses by blunting illness severity and spread until vaccines and virus-specific antivirals are developed. The nucleobase favipiravir, often discussed as a broad-spectrum inhibitor, was not effective in recent clinical trials involving patients infected with Ebola virus or SARS-CoV-2. A drawback of favipiravir use is its rapid clearance before conversion to its active nucleoside-5′-triphosphate form. In this work, we report a synergistic reduction of flavivirus (dengue, Zika), orthomyxovirus (influenza A), and coronavirus (HCoV-OC43 and SARS-CoV-2) replication when the nucleobases favipiravir or T-1105 were combined with the antimetabolite 6-methylmercaptopurine riboside (6MMPr). The 6MMPr/T-1105 combination increased the C-U and G-A mutation frequency compared to treatment with T-1105 or 6MMPr alone. A further analysis revealed that the 6MMPr/T-1105 co-treatment reduced cellular purine nucleotide triphosphate synthesis and increased conversion of the antiviral nucleobase to its nucleoside-5′-monophosphate, -diphosphate, and -triphosphate forms. The 6MMPr co-treatment specifically increased production of the active antiviral form of the nucleobases (but not corresponding nucleosides) while also reducing levels of competing cellular NTPs to produce the synergistic effect. This in-depth work establishes a foundation for development of small molecules as possible co-treatments with nucleobases like favipiravir in response to emerging RNA virus infections. Full article

(This article belongs to the Special Issue Antivirals for Newly Emerging Viral Diseases of Global Importance)

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15 pages, 1991 KiB

Open AccessArticle

The Methanolic Extract of Perilla frutescens Robustly Restricts Ebola Virus Glycoprotein-Mediated Entry

by Yu-Ting Kuo, Ching-Hsuan Liu, Angela Corona, Elisa Fanunza, Enzo Tramontano and Liang-Tzung Lin

Viruses 2021, 13(9), 1793; https://doi.org/10.3390/v13091793 - 8 Sep 2021

Cited by 7 | Viewed by 3511

Abstract

Ebola virus (EBOV), one of the most infectious human viruses and a leading cause of viral hemorrhagic fever, imposes a potential public health threat with several recent outbreaks. Despite the difficulties associated with working with this pathogen in biosafety level-4 containment, a protective [...] Read more.

Ebola virus (EBOV), one of the most infectious human viruses and a leading cause of viral hemorrhagic fever, imposes a potential public health threat with several recent outbreaks. Despite the difficulties associated with working with this pathogen in biosafety level-4 containment, a protective vaccine and antiviral therapeutic were recently approved. However, the high mortality rate of EBOV infection underscores the necessity to continuously identify novel antiviral strategies to help expand the scope of prophylaxis/therapeutic management against future outbreaks. This includes identifying antiviral agents that target EBOV entry, which could improve the management of EBOV infection. Herein, using EBOV glycoprotein (GP)-pseudotyped particles, we screened a panel of natural medicinal extracts, and identified the methanolic extract of Perilla frutescens (PFME) as a robust inhibitor of EBOV entry. We show that PFME dose-dependently impeded EBOV GP-mediated infection at non-cytotoxic concentrations, and exerted the most significant antiviral activity when both the extract and the pseudoparticles are concurrently present on the host cells. Specifically, we demonstrate that PFME could block viral attachment and neutralize the cell-free viral particles. Our results, therefore, identified PFME as a potent inhibitor of EBOV entry, which merits further evaluation for development as a therapeutic strategy against EBOV infection. Full article

(This article belongs to the Special Issue Antivirals for Newly Emerging Viral Diseases of Global Importance)

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15 pages, 1935 KiB

Open AccessArticle

A Novel Frameshifting Inhibitor Having Antiviral Activity against Zoonotic Coronaviruses

by Dae-Gyun Ahn, Gun Young Yoon, Sunhee Lee, Keun Bon Ku, Chonsaeng Kim, Kyun-Do Kim, Young-Chan Kwon, Geon-Woo Kim, Bum-Tae Kim and Seong-Jun Kim

Viruses 2021, 13(8), 1639; https://doi.org/10.3390/v13081639 - 18 Aug 2021

Cited by 10 | Viewed by 3832

Abstract

Recent outbreaks of zoonotic coronaviruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have caused tremendous casualties and great economic shock. Although some repurposed drugs have shown potential therapeutic efficacy in clinical trials, specific therapeutic [...] Read more.

Recent outbreaks of zoonotic coronaviruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have caused tremendous casualties and great economic shock. Although some repurposed drugs have shown potential therapeutic efficacy in clinical trials, specific therapeutic agents targeting coronaviruses have not yet been developed. During coronavirus replication, a replicase gene cluster, including RNA-dependent RNA polymerase (RdRp), is alternatively translated via a process called -1 programmed ribosomal frameshift (−1 PRF) by an RNA pseudoknot structure encoded in viral RNAs. The coronavirus frameshifting has been identified previously as a target for antiviral therapy. In this study, the frameshifting efficiencies of MERS-CoV, SARS-CoV and SARS-CoV-2 were determined using an in vitro −1 PRF assay system. Our group has searched approximately 9689 small molecules to identify potential −1 PRF inhibitors. Herein, we found that a novel compound, 2-(5-acetylthiophen-2yl)furo[2,3-b]quinoline (KCB261770), inhibits the frameshifting of MERS-CoV and effectively suppresses viral propagation in MERS-CoV-infected cells. The inhibitory effects of 87 derivatives of furo[2,3-b]quinolines were also examined showing less prominent inhibitory effect when compared to compound KCB261770. We demonstrated that KCB261770 inhibits the frameshifting without suppressing cap-dependent translation. Furthermore, this compound was able to inhibit the frameshifting, to some extent, of SARS-CoV and SARS-CoV-2. Therefore, the novel compound 2-(5-acetylthiophen-2yl)furo[2,3-b]quinoline may serve as a promising drug candidate to interfere with pan-coronavirus frameshifting. Full article

(This article belongs to the Special Issue Antivirals for Newly Emerging Viral Diseases of Global Importance)

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12 pages, 2416 KiB

Open AccessArticle

Noble Metal Organometallic Complexes Display Antiviral Activity against SARS-CoV-2

by Christina Chuong, Christine M. DuChane, Emily M. Webb, Pallavi Rai, Jeffrey M. Marano, Chad M. Bernier, Joseph S. Merola and James Weger-Lucarelli

Viruses 2021, 13(6), 980; https://doi.org/10.3390/v13060980 - 25 May 2021

Cited by 21 | Viewed by 4277

Abstract

SARS-CoV-2 emerged in 2019 as a devastating viral pathogen with no available preventative or treatment to control what led to the current global pandemic. The continued spread of the virus and increasing death toll necessitate the development of effective antiviral treatments to combat [...] Read more.

SARS-CoV-2 emerged in 2019 as a devastating viral pathogen with no available preventative or treatment to control what led to the current global pandemic. The continued spread of the virus and increasing death toll necessitate the development of effective antiviral treatments to combat this virus. To this end, we evaluated a new class of organometallic complexes as potential antivirals. Our findings demonstrate that two pentamethylcyclopentadienyl (Cp*) rhodium piano stool complexes, Cp*Rh(1,3-dicyclohexylimidazol-2-ylidene)Cl₂ (complex 2) and Cp*Rh(dipivaloylmethanato)Cl (complex 4), have direct virucidal activity against SARS-CoV-2. Subsequent in vitro testing suggests that complex 4 is the more stable and effective complex and demonstrates that both 2 and 4 have low toxicity in Vero E6 and Calu-3 cells. The results presented here highlight the potential application of organometallic complexes as antivirals and support further investigation into their activity. Full article

(This article belongs to the Special Issue Antivirals for Newly Emerging Viral Diseases of Global Importance)

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15 pages, 3384 KiB

Open AccessArticle

Identification of the SHREK Family of Proteins as Broad-Spectrum Host Antiviral Factors

by Deemah Dabbagh, Sijia He, Brian Hetrick, Linda Chilin, Ali Andalibi and Yuntao Wu

Viruses 2021, 13(5), 832; https://doi.org/10.3390/v13050832 - 4 May 2021

Cited by 7 | Viewed by 4650

Abstract

Mucins and mucin-like molecules are highly glycosylated, high-molecular-weight cell surface proteins that possess a semi-rigid and highly extended extracellular domain. P-selectin glycoprotein ligand-1 (PSGL-1), a mucin-like glycoprotein, has recently been found to restrict HIV-1 infectivity through virion incorporation that sterically hinders virus particle [...] Read more.

Mucins and mucin-like molecules are highly glycosylated, high-molecular-weight cell surface proteins that possess a semi-rigid and highly extended extracellular domain. P-selectin glycoprotein ligand-1 (PSGL-1), a mucin-like glycoprotein, has recently been found to restrict HIV-1 infectivity through virion incorporation that sterically hinders virus particle attachment to target cells. Here, we report the identification of a family of antiviral cellular proteins, named the Surface-Hinged, Rigidly-Extended Killer (SHREK) family of virion inactivators (PSGL-1, CD43, TIM-1, CD34, PODXL1, PODXL2, CD164, MUC1, MUC4, and TMEM123) that share similar structural characteristics with PSGL-1. We demonstrate that SHREK proteins block HIV-1 infectivity by inhibiting virus particle attachment to target cells. In addition, we demonstrate that SHREK proteins are broad-spectrum host antiviral factors that block the infection of diverse viruses such as influenza A. Furthermore, we demonstrate that a subset of SHREKs also blocks the infectivity of a hybrid alphavirus-SARS-CoV-2 (Ha-CoV-2) pseudovirus. These results suggest that SHREK proteins may be a part of host innate immunity against enveloped viruses. Full article

(This article belongs to the Special Issue Antivirals for Newly Emerging Viral Diseases of Global Importance)

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Review

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21 pages, 411 KiB

Open AccessReview

Therapeutic Strategies against Ebola Virus Infection

by Ching-Hsuan Liu, Yee-Tung Hu, Shu Hui Wong and Liang-Tzung Lin

Viruses 2022, 14(3), 579; https://doi.org/10.3390/v14030579 - 11 Mar 2022

Cited by 17 | Viewed by 5276

Abstract

Since the 2014–2016 epidemic, Ebola virus (EBOV) has spread to several countries and has become a major threat to global health. EBOV is a risk group 4 pathogen, which imposes significant obstacles for the development of countermeasures against the virus. Efforts have been [...] Read more.

Since the 2014–2016 epidemic, Ebola virus (EBOV) has spread to several countries and has become a major threat to global health. EBOV is a risk group 4 pathogen, which imposes significant obstacles for the development of countermeasures against the virus. Efforts have been made to develop anti-EBOV immunization and therapeutics, with three vaccines and two antibody-based therapeutics approved in recent years. Nonetheless, the high fatality of Ebola virus disease highlights the need to continuously develop antiviral strategies for the future management of EBOV outbreaks in conjunction with vaccination programs. This review aims to highlight potential EBOV therapeutics and their target(s) of inhibition, serving as a summary of the literature to inform readers of the novel candidates available in the continued search for EBOV antivirals. Full article

(This article belongs to the Special Issue Antivirals for Newly Emerging Viral Diseases of Global Importance)

17 pages, 3009 KiB

Open AccessReview

Peering into Avian Influenza A(H5N8) for a Framework towards Pandemic Preparedness

by Joshua Yi Yeo and Samuel Ken-En Gan

Viruses 2021, 13(11), 2276; https://doi.org/10.3390/v13112276 - 15 Nov 2021

Cited by 7 | Viewed by 6486

Abstract

2014 marked the first emergence of avian influenza A(H5N8) in Jeonbuk Province, South Korea, which then quickly spread worldwide. In the midst of the 2020–2021 H5N8 outbreak, it spread to domestic poultry and wild waterfowl shorebirds, leading to the first human infection in [...] Read more.

2014 marked the first emergence of avian influenza A(H5N8) in Jeonbuk Province, South Korea, which then quickly spread worldwide. In the midst of the 2020–2021 H5N8 outbreak, it spread to domestic poultry and wild waterfowl shorebirds, leading to the first human infection in Astrakhan Oblast, Russia. Despite being clinically asymptomatic and without direct human-to-human transmission, the World Health Organization stressed the need for continued risk assessment given the nature of Influenza to reassort and generate novel strains. Given its promiscuity and easy cross to humans, the urgency to understand the mechanisms of possible species jumping to avert disastrous pandemics is increasing. Addressing the epidemiology of H5N8, its mechanisms of species jumping and its implications, mutational and reassortment libraries can potentially be built, allowing them to be tested on various models complemented with deep-sequencing and automation. With knowledge on mutational patterns, cellular pathways, drug resistance mechanisms and effects of host proteins, we can be better prepared against H5N8 and other influenza A viruses. Full article

(This article belongs to the Special Issue Antivirals for Newly Emerging Viral Diseases of Global Importance)

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12 pages, 1024 KiB

Open AccessReview

Antiviral Bioactive Compounds of Mushrooms and Their Antiviral Mechanisms: A Review

by Dong Joo Seo and Changsun Choi

Viruses 2021, 13(2), 350; https://doi.org/10.3390/v13020350 - 23 Feb 2021

Cited by 60 | Viewed by 9124

Abstract

Mushrooms are used in their natural form as a food supplement and food additive. In addition, several bioactive compounds beneficial for human health have been derived from mushrooms. Among them, polysaccharides, carbohydrate-binding protein, peptides, proteins, enzymes, polyphenols, triterpenes, triterpenoids, and several other compounds [...] Read more.

Mushrooms are used in their natural form as a food supplement and food additive. In addition, several bioactive compounds beneficial for human health have been derived from mushrooms. Among them, polysaccharides, carbohydrate-binding protein, peptides, proteins, enzymes, polyphenols, triterpenes, triterpenoids, and several other compounds exert antiviral activity against DNA and RNA viruses. Their antiviral targets were mostly virus entry, viral genome replication, viral proteins, and cellular proteins and influenced immune modulation, which was evaluated through pre-, simultaneous-, co-, and post-treatment in vitro and in vivo studies. In particular, they treated and relieved the viral diseases caused by herpes simplex virus, influenza virus, and human immunodeficiency virus (HIV). Some mushroom compounds that act against HIV, influenza A virus, and hepatitis C virus showed antiviral effects comparable to those of antiviral drugs. Therefore, bioactive compounds from mushrooms could be candidates for treating viral infections. Full article

(This article belongs to the Special Issue Antivirals for Newly Emerging Viral Diseases of Global Importance)

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