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Pharmaceutics
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Drugs for Antiviral Combination Therapy
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Drugs for Antiviral Combination Therapy

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biologics and Biosimilars".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 17519

Special Issue Editors

Dr. Sebastian Schloer

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Guest Editor
Leibniz Institute for Experimental Virology, Martinistraße 52, D-20251 Hamburg, Germany
Interests: virus–host interaction; innate immunity; antiviral research; drug repurposing
Prof. Dr. Stephan Ludwig

E-Mail Website
Guest Editor
Institute of Virology, University of Münster, 48149 Münster, Germany
Interests: interaction of influenza viruses and other respiratory pathogens with the host cells and immune system; innate immune mechanisms in acute virus infections; host-targeted antivirals against respiratory viruses
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Ursula Rescher

E-Mail Website
Guest Editor
Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, University of Münster, Von-Esmarch-Straße 56, D-48149 Münster, Germany
Interests: host–pathogen interactions; host intracellular compartments; drug repurposing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The host–virus interplay and host signaling cascades involved in the entry and propagation of novel and emerging viruses are far from being understood. Many direct-acting antivirals or host-directed drugs are currently under investigation to estimate their antiviral potential. Using more than one antiviral might potentiate the antiviral effect and preserve sensitivity to the drugs. A combination of drugs that target different steps of the virus life cycle is a promising clinical approach as already confirmed in HIV or HCV therapy. The scope of this Special Issue is to explore novel virus and cellular key sensors and effectors involved in virus infection as novel pharmacological targets, evaluate respective drugs, and assess their effects when given in combination.

We are looking forward to receiving your contributions.

Dr. Sebastian Schloer
Prof. Dr. Stephan Ludwig
Prof. Dr. Ursula Rescher
Guest Editors

Manuscript Submission Information

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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. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

  • antivirals
  • virus-directed drugs
  • host-directed drugs
  • drug repurposing
  • combination therapy

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Published Papers (7 papers)

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Research

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27 pages, 4436 KiB  
Article
T-705-Derived Prodrugs Show High Antiviral Efficacies against a Broad Range of Influenza A Viruses with Synergistic Effects When Combined with Oseltamivir
by Benedikt Ganter, Martin Zickler, Johanna Huchting, Matthias Winkler, Anna Lüttjohann, Chris Meier, Gülsah Gabriel and Sebastian Beck
Pharmaceutics 2023, 15(6), 1732; https://doi.org/10.3390/pharmaceutics15061732 - 14 Jun 2023
Viewed by 1796
Abstract
Emerging influenza A viruses (IAV) bear the potential to cause pandemics with unpredictable consequences for global human health. In particular, the WHO has declared avian H5 and H7 subtypes as high-risk candidates, and continuous surveillance of these viruses as well as the development [...] Read more.
Emerging influenza A viruses (IAV) bear the potential to cause pandemics with unpredictable consequences for global human health. In particular, the WHO has declared avian H5 and H7 subtypes as high-risk candidates, and continuous surveillance of these viruses as well as the development of novel, broadly acting antivirals, are key for pandemic preparedness. In this study, we sought to design T-705 (Favipiravir) related inhibitors that target the RNA-dependent RNA polymerase and evaluate their antiviral efficacies against a broad range of IAVs. Therefore, we synthesized a library of derivatives of T-705 ribonucleoside analogues (called T-1106 pronucleotides) and tested their ability to inhibit both seasonal and highly pathogenic avian influenza viruses in vitro. We further showed that diphosphate (DP) prodrugs of T-1106 are potent inhibitors of H1N1, H3N2, H5N1, and H7N9 IAV replication. Importantly, in comparison to T-705, these DP derivatives achieved 5- to 10-fold higher antiviral activity and were non-cytotoxic at the therapeutically active concentrations. Moreover, our lead DP prodrug candidate showed drug synergy with the neuraminidase inhibitor oseltamivir, thus opening up another avenue for combinational antiviral therapy against IAV infections. Our findings may serve as a basis for further pre-clinical development of T-1106 prodrugs as an effective countermeasure against emerging IAVs with pandemic potential. Full article
(This article belongs to the Special Issue Drugs for Antiviral Combination Therapy)
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13 pages, 1903 KiB  
Article
Effects of Statin Combinations on Zika Virus Infection in Vero Cells
by Erica Españo and Jeong-Ki Kim
Pharmaceutics 2023, 15(1), 50; https://doi.org/10.3390/pharmaceutics15010050 - 23 Dec 2022
Cited by 5 | Viewed by 1883
Abstract
The Zika virus (ZIKV) remains a global health concern. Thus far, no antiviral or vaccine has been approved to prevent or treat ZIKV infection. In a previous study, we found that lipophilic statins can inhibit ZIKV production in Vero cells. These statins appear [...] Read more.
The Zika virus (ZIKV) remains a global health concern. Thus far, no antiviral or vaccine has been approved to prevent or treat ZIKV infection. In a previous study, we found that lipophilic statins can inhibit ZIKV production in Vero cells. These statins appear to have different potencies against ZIKV infection. Here, we determined whether combinations of statins would have synergistic effects to maximize the efficacy of the statins and to reduce potential side effects. Specifically, we used a modified fixed-ratio assay for the combinations of atorvastatin (ATO) or fluvastatin (FLU) with mevastatin (MEV) or simvastatin (SIM). All combinations with MEV tended towards synergy, especially with higher fractions of MEV in the combinations. The ATO + SIM combination tended towards additivity. The FLU + SIM combination also tended towards additivity except for one combination which had the highest fraction of FLU over SIM among the tested combinations. Overall, certain combinations of ATO or FLU with SIM or MEV may be synergistic. More exhaustive combinatorial assays in vitro and in vivo could help define whether combining lipophilic statins would be beneficial and safe for treating ZIKV infections. Full article
(This article belongs to the Special Issue Drugs for Antiviral Combination Therapy)
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11 pages, 1971 KiB  
Article
Pharmacological Validation of Long-Term Treatment with Antiretroviral Drugs in a Model of SIV-Infected Non-Human Primates
by Thibaut Gelé, Hélène Gouget, Nathalie Dereuddre-Bosquet, Valérie Furlan, Roger Le Grand, Olivier Lambotte, Delphine Desjardins and Aurélie Barrail-Tran
Pharmaceutics 2022, 14(11), 2282; https://doi.org/10.3390/pharmaceutics14112282 - 25 Oct 2022
Cited by 1 | Viewed by 1838
Abstract
The development of animal models undergoing long-term antiretroviral treatment (ART) makes it possible to understand a number of immunological, virological, and pharmacological issues, key factors in the management of HIV infection. We aimed to pharmacologically validate a non-human primate (NHP) model treated in [...] Read more.
The development of animal models undergoing long-term antiretroviral treatment (ART) makes it possible to understand a number of immunological, virological, and pharmacological issues, key factors in the management of HIV infection. We aimed to pharmacologically validate a non-human primate (NHP) model treated in the long term with antiretroviral drugs after infection with the pathogenic SIVmac251 strain. A single-dose pharmacokinetic study of tenofovir disoproxil fumarate, emtricitabine, and dolutegravir was first conducted on 13 non-infected macaques to compare three different routes of administration. Then, 12 simian immunodeficiency virus (SIV)-infected (SIV+) macaques were treated with the same regimen for two years. Drug monitoring, virological efficacy, and safety were evaluated throughout the study. For the single-dose pharmacokinetic study, 24-h post-dose plasma concentrations for all macaques were above or close to 90% inhibitory concentrations and consistent with human data. During the two-year follow-up, the pharmacological data were consistent with those observed in humans, with low inter- and intra-individual variability. Rapid and sustained virological efficacy was observed for all macaques, with a good safety profile. Overall, our SIV+ NHP model treated with the ART combination over a two-year period is suitable for investigating the question of pharmacological sanctuaries in HIV infection and exploring strategies for an HIV cure. Full article
(This article belongs to the Special Issue Drugs for Antiviral Combination Therapy)
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12 pages, 8935 KiB  
Communication
The MEK1/2 Inhibitor ATR-002 (Zapnometinib) Synergistically Potentiates the Antiviral Effect of Direct-Acting Anti-SARS-CoV-2 Drugs
by André Schreiber, Benjamin Ambrosy, Oliver Planz, Sebastian Schloer, Ursula Rescher and Stephan Ludwig
Pharmaceutics 2022, 14(9), 1776; https://doi.org/10.3390/pharmaceutics14091776 - 25 Aug 2022
Cited by 9 | Viewed by 2702
Abstract
The coronavirus disease 2019 (COVID-19) represents a global public health burden. In addition to vaccination, safe and efficient antiviral treatment strategies to restrict the viral spread within the patient are urgently needed. An alternative approach to a single-drug therapy is the combinatory use [...] Read more.
The coronavirus disease 2019 (COVID-19) represents a global public health burden. In addition to vaccination, safe and efficient antiviral treatment strategies to restrict the viral spread within the patient are urgently needed. An alternative approach to a single-drug therapy is the combinatory use of virus- and host-targeted antivirals, leading to a synergistic boost of the drugs’ impact. In this study, we investigated the property of the MEK1/2 inhibitor ATR-002’s (zapnometinib) ability to potentiate the effect of direct-acting antivirals (DAA) against SARS-CoV-2 on viral replication. Treatment combinations of ATR-002 with nucleoside inhibitors Molnupiravir and Remdesivir or 3C-like protease inhibitors Nirmatrelvir and Ritonavir, the ingredients of the drug Paxlovid, were examined in Calu-3 cells to evaluate the advantage of their combinatory use against a SARS-CoV-2 infection. Synergistic effects could be observed for all tested combinations of ATR-002 with DAAs, as calculated by four different reference models in a concentration range that was very well-tolerated by the cells. Our results show that ATR-002 has the potential to act synergistically in combination with direct-acting antivirals, allowing for a reduction in the effective concentrations of the individual drugs and reducing side effects. Full article
(This article belongs to the Special Issue Drugs for Antiviral Combination Therapy)
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17 pages, 7803 KiB  
Article
The Synergistic Inhibition of Coronavirus Replication and Induced Cytokine Production by Ciclesonide and the Tylophorine-Based Compound Dbq33b
by Yue-Zhi Lee, Hsing-Yu Hsu, Cheng-Wei Yang, Yi-Ling Lin, Sui-Yuan Chang, Ruey-Bing Yang, Jian-Jong Liang, Tai-Ling Chao, Chun-Che Liao, Han-Chieh Kao, Jang-Yang Chang, Huey-Kang Sytwu, Chiung-Tong Chen and Shiow-Ju Lee
Pharmaceutics 2022, 14(7), 1511; https://doi.org/10.3390/pharmaceutics14071511 - 21 Jul 2022
Cited by 2 | Viewed by 2244 | Correction
Abstract
Ciclesonide is an inhaled corticosteroid used to treat asthma and has been repurposed as a treatment for mildly ill COVID-19 patients, but its precise mechanism of action is unclear. Herein, we report that ciclesonide blocks the coronavirus-induced production of the cytokines IL-6, IL-8, [...] Read more.
Ciclesonide is an inhaled corticosteroid used to treat asthma and has been repurposed as a treatment for mildly ill COVID-19 patients, but its precise mechanism of action is unclear. Herein, we report that ciclesonide blocks the coronavirus-induced production of the cytokines IL-6, IL-8, and MCP-1 by increasing IκBα protein levels and significantly decreasing p65 nuclear translocation. Furthermore, we found that the combination of ciclesonide and dbq33b, a potent tylophorine-based coronavirus inhibitor that affects coronavirus-induced NF-κB activation a little, additively and synergistically decreased coronavirus-induced IL-6, IL-8, and MCP-1 cytokine levels, and synergistically inhibited the replication of both HCoV-OC43 and SARS-CoV-2. Collectively, the combination of ciclesonide and dbq33b merits consideration as a treatment for COVID-19 patients who may otherwise be overwhelmed by high viral loads and an NF-κB-mediated cytokine storm. Full article
(This article belongs to the Special Issue Drugs for Antiviral Combination Therapy)
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Review

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33 pages, 866 KiB  
Review
Uses and Challenges of Antiviral Polyclonal and Monoclonal Antibody Therapies
by Evi B. Struble, Jonathan M. O. Rawson, Tzanko Stantchev, Dorothy Scott and Marjorie A. Shapiro
Pharmaceutics 2023, 15(5), 1538; https://doi.org/10.3390/pharmaceutics15051538 - 19 May 2023
Cited by 8 | Viewed by 3637
Abstract
Viral diseases represent a major public health concerns and ever-present risks for developing into future pandemics. Antiviral antibody therapeutics, either alone or in combination with other therapies, emerged as valuable preventative and treatment options, including during global emergencies. Here we will discuss polyclonal [...] Read more.
Viral diseases represent a major public health concerns and ever-present risks for developing into future pandemics. Antiviral antibody therapeutics, either alone or in combination with other therapies, emerged as valuable preventative and treatment options, including during global emergencies. Here we will discuss polyclonal and monoclonal antiviral antibody therapies, focusing on the unique biochemical and physiological properties that make them well-suited as therapeutic agents. We will describe the methods of antibody characterization and potency assessment throughout development, highlighting similarities and differences between polyclonal and monoclonal products as appropriate. In addition, we will consider the benefits and challenges of antiviral antibodies when used in combination with other antibodies or other types of antiviral therapeutics. Lastly, we will discuss novel approaches to the characterization and development of antiviral antibodies and identify areas that would benefit from additional research. Full article
(This article belongs to the Special Issue Drugs for Antiviral Combination Therapy)
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20 pages, 1308 KiB  
Review
Dengue, West Nile, and Zika Viruses: Potential Novel Antiviral Biologics Drugs Currently at Discovery and Preclinical Development Stages
by Ivo C. Martins, Rafaela C. Ricardo and Nuno C. Santos
Pharmaceutics 2022, 14(11), 2535; https://doi.org/10.3390/pharmaceutics14112535 - 20 Nov 2022
Cited by 15 | Viewed by 2623
Abstract
Dengue, West Nile and Zika viruses are vector-borne flaviviruses responsible for numerous disease outbreaks in both Hemispheres. Despite relatively low mortality, infection may lead to potentially severe situations such as (depending on the virus): hypovolemic shock, encephalitis, acute flaccid paralysis, Guillain-Barré syndrome, congenital [...] Read more.
Dengue, West Nile and Zika viruses are vector-borne flaviviruses responsible for numerous disease outbreaks in both Hemispheres. Despite relatively low mortality, infection may lead to potentially severe situations such as (depending on the virus): hypovolemic shock, encephalitis, acute flaccid paralysis, Guillain-Barré syndrome, congenital malformations (e.g., microcephaly) and, in some situations, death. Moreover, outbreaks also have major socioeconomic repercussions, especially in already vulnerable societies. Thus far, only generic symptoms relief is possible, as there are no specific treatments available yet. Dengvaxia was the world’s first dengue vaccine. However, it is not fully effective. Prophylactic approaches against West Nile and Zika viruses are even more limited. Therefore, therapeutic strategies are required and will be discussed hereafter. We will first briefly present these viruses’ epidemiology, life cycle and structure. Then, we introduce the clinical presentation, diagnosis approaches and available vaccines. Finally, we list and discuss promising compounds at discovery and preclinical development stages already deposited at the GlobalData database and divided into three main types, according to therapeutic molecule: antibody-based, peptide-based molecules and, other compounds. To conclude, we discuss and compare promising developments, useful for future therapies against these three flaviviruses of major concern to human health. Full article
(This article belongs to the Special Issue Drugs for Antiviral Combination Therapy)
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