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1.
iScience ; 25(4), 2022.
Article in English | EuropePMC | ID: covidwho-1781054

ABSTRACT

Summary Broadly effective antiviral therapies must be developed to be ready for clinical trials, which should begin soon after the emergence of new life-threatening viruses. Here, we pave the way towards this goal by reviewing conserved druggable virus-host interactions, mechanisms of action, immunomodulatory properties of available broad-spectrum antivirals (BSAs), routes of BSA delivery, and interactions of BSAs with other antivirals. Based on the review, we concluded that the range of indications of BSAs can be expanded, and new pan- and cross-viral mono- and combinational therapies can be developed. We have also developed a new scoring algorithm that can help identify the most promising few of the thousands of potential BSAs and BSA-containing drug cocktails (BCCs) to prioritize their development during the critical period between the identification of a new virus and the development of virus-specific vaccines, drugs, and therapeutic antibodies. Graphical Pharmaceutical preparation;Pharmaceutical science;Pharmacology;Chemistry

2.
Viruses ; 14(2)2022 02 01.
Article in English | MEDLINE | ID: covidwho-1715768

ABSTRACT

Viral diseases consistently pose a substantial economic and public health burden worldwide [...].


Subject(s)
Antiviral Agents/pharmacology , Virus Diseases/drug therapy , Humans , Virus Diseases/virology , Virus Physiological Phenomena , Viruses/classification , Viruses/drug effects , Viruses/genetics
3.
Viruses ; 13(12)2021 12 11.
Article in English | MEDLINE | ID: covidwho-1572663

ABSTRACT

BACKGROUND: There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. METHODS: Here, we tested the antiviral properties of interferons (IFNs), alone and with other drugs in vitro. RESULTS: While IFNs alone were insufficient to completely abolish replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), IFNα, in combination with remdesivir, EIDD-2801, camostat, cycloheximide, or convalescent serum, proved to be more effective. Transcriptome and metabolomic analyses revealed that the IFNα-remdesivir combination suppressed SARS-CoV-2-mediated changes in Calu-3 cells and lung organoids, although it altered the homeostasis of uninfected cells and organoids. We also demonstrated that IFNα combinations with sofosbuvir, telaprevir, NITD008, ribavirin, pimodivir, or lamivudine were effective against HCV, HEV, FLuAV, or HIV at lower concentrations, compared to monotherapies. CONCLUSIONS: Altogether, our results indicated that IFNα can be combined with drugs that affect viral RNA transcription, protein synthesis, and processing to make synergistic combinations that can be attractive targets for further pre-clinical and clinical development against emerging and re-emerging viral infections.


Subject(s)
Antiviral Agents/pharmacology , Interferon-alpha/pharmacology , SARS-CoV-2/drug effects , Cell Line , Drug Synergism , Humans , Lung/drug effects , Lung/metabolism , Lung/virology , Metabolome/drug effects , Organoids , RNA, Viral/biosynthesis , RNA, Viral/drug effects , Signal Transduction/drug effects , Transcriptome/drug effects , Virus Replication/drug effects , Viruses/classification , Viruses/drug effects
4.
Viruses ; 13(9)2021 09 04.
Article in English | MEDLINE | ID: covidwho-1478110

ABSTRACT

SARS-CoV-2 and its vaccine/immune-escaping variants continue to pose a serious threat to public health due to a paucity of effective, rapidly deployable, and widely available treatments. Here, we address these challenges by combining Pegasys (IFNα) and nafamostat to effectively suppress SARS-CoV-2 infection in cell culture and hamsters. Our results indicate that Serpin E1 is an important mediator of the antiviral activity of IFNα and that both Serpin E1 and nafamostat can target the same cellular factor TMPRSS2, which plays a critical role in viral replication. The low doses of the drugs in combination may have several clinical advantages, including fewer adverse events and improved patient outcome. Thus, our study may provide a proactive solution for the ongoing pandemic and potential future coronavirus outbreaks, which is still urgently required in many parts of the world.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzamidines/pharmacology , COVID-19/metabolism , COVID-19/virology , Guanidines/pharmacology , Interferon-alpha/pharmacology , SARS-CoV-2/drug effects , Serine Endopeptidases/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzamidines/therapeutic use , COVID-19/drug therapy , Cricetinae , Disease Models, Animal , Drug Therapy, Combination , Female , Guanidines/therapeutic use , Host-Pathogen Interactions/drug effects , Humans , Interferon-alpha/therapeutic use , Virus Replication/drug effects
5.
Viruses ; 13(9)2021 09 04.
Article in English | MEDLINE | ID: covidwho-1390793

ABSTRACT

SARS-CoV-2 and its vaccine/immune-escaping variants continue to pose a serious threat to public health due to a paucity of effective, rapidly deployable, and widely available treatments. Here, we address these challenges by combining Pegasys (IFNα) and nafamostat to effectively suppress SARS-CoV-2 infection in cell culture and hamsters. Our results indicate that Serpin E1 is an important mediator of the antiviral activity of IFNα and that both Serpin E1 and nafamostat can target the same cellular factor TMPRSS2, which plays a critical role in viral replication. The low doses of the drugs in combination may have several clinical advantages, including fewer adverse events and improved patient outcome. Thus, our study may provide a proactive solution for the ongoing pandemic and potential future coronavirus outbreaks, which is still urgently required in many parts of the world.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzamidines/pharmacology , COVID-19/metabolism , COVID-19/virology , Guanidines/pharmacology , Interferon-alpha/pharmacology , SARS-CoV-2/drug effects , Serine Endopeptidases/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzamidines/therapeutic use , COVID-19/drug therapy , Cricetinae , Disease Models, Animal , Drug Therapy, Combination , Female , Guanidines/therapeutic use , Host-Pathogen Interactions/drug effects , Humans , Interferon-alpha/therapeutic use , Virus Replication/drug effects
6.
Viruses ; 13(4)2021 04 09.
Article in English | MEDLINE | ID: covidwho-1178434

ABSTRACT

Therapeutic options for coronaviruses remain limited. To address this unmet medical need, we screened 5406 compounds, including United States Food and Drug Administration (FDA)-approved drugs and bioactives, for activity against a South Korean Middle East respiratory syndrome coronavirus (MERS-CoV) clinical isolate. Among 221 identified hits, 54 had therapeutic indexes (TI) greater than 6, representing effective drugs. The time-of-addition studies with selected drugs demonstrated eight and four FDA-approved drugs which acted on the early and late stages of the viral life cycle, respectively. Confirmed hits included several cardiotonic agents (TI > 100), atovaquone, an anti-malarial (TI > 34), and ciclesonide, an inhalable corticosteroid (TI > 6). Furthermore, utilizing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we tested combinations of remdesivir with selected drugs in Vero-E6 and Calu-3 cells, in lung organoids, and identified ciclesonide, nelfinavir, and camostat to be at least additive in vitro. Our results identify potential therapeutic options for MERS-CoV infections, and provide a basis to treat coronavirus disease 2019 (COVID-19) and other coronavirus-related illnesses.


Subject(s)
Antiviral Agents/pharmacology , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/isolation & purification , SARS-CoV-2/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , COVID-19/drug therapy , Coronavirus Infections/virology , Drug Approval , Drug Evaluation, Preclinical , Drug Repositioning , Drug Synergism , Humans , Life Cycle Stages/drug effects , Middle East Respiratory Syndrome Coronavirus/growth & development , Small Molecule Libraries/pharmacology
7.
Cell Rep Med ; 2(1): 100189, 2021 01 19.
Article in English | MEDLINE | ID: covidwho-1065662

ABSTRACT

The SARS-CoV-2 proteome shares regions of conservation with endemic human coronaviruses (CoVs), but it remains unknown to what extent these may be cross-recognized by the antibody response. Here, we study cross-reactivity using a highly multiplexed peptide assay (PepSeq) to generate an epitope-resolved view of IgG reactivity across all human CoVs in both COVID-19 convalescent and negative donors. PepSeq resolves epitopes across the SARS-CoV-2 Spike and Nucleocapsid proteins that are commonly targeted in convalescent donors, including several sites also recognized in some uninfected controls. By comparing patterns of homologous reactivity between CoVs and using targeted antibody-depletion experiments, we demonstrate that SARS-CoV-2 elicits antibodies that cross-recognize pandemic and endemic CoV antigens at two Spike S2 subunit epitopes. We further show that these cross-reactive antibodies preferentially bind endemic homologs. Our findings highlight sites at which the SARS-CoV-2 response appears to be shaped by previous CoV exposures and which have the potential to raise broadly neutralizing responses.

8.
Viruses ; 12(10):1178, 2020.
Article in English | MDPI | ID: covidwho-875311

ABSTRACT

Combination therapies have become a standard for the treatment for HIV and hepatitis C virus (HCV) infections. They are advantageous over monotherapies due to better efficacy, reduced toxicity, as well as the ability to prevent the development of resistant viral strains and to treat viral co-infections. Here, we identify new synergistic combinations against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), echovirus 1 (EV1), hepatitis C virus (HCV) and human immunodeficiency virus 1 (HIV-1) in vitro. We observed synergistic activity of nelfinavir with convalescent serum and with purified neutralizing antibody 23G7 against SARS-CoV-2 in human lung epithelial Calu-3 cells. We also demonstrated synergistic activity of nelfinavir with EIDD-2801 or remdesivir in Calu-3 cells. In addition, we showed synergistic activity of vemurafenib with emetine, homoharringtonine, anisomycin, or cycloheximide against EV1 infection in human lung epithelial A549 cells. We also found that combinations of sofosbuvir with brequinar or niclosamide are synergistic against HCV infection in hepatocyte-derived Huh-7.5 cells, and that combinations of monensin with lamivudine or tenofovir are synergistic against HIV-1 infection in human cervical TZM-bl cells. These results indicate that synergy is achieved when a virus-directed antiviral is combined with another virus- or host-directed agent. Finally, we present an online resource that summarizes novel and known antiviral drug combinations and their developmental status.

9.
Viruses ; 12(6)2020 06 13.
Article in English | MEDLINE | ID: covidwho-602214

ABSTRACT

As of June 2020, the number of people infected with severe acute respiratory coronavirus 2 (SARS-CoV-2) continues to skyrocket, with more than 6.7 million cases worldwide. Both the World Health Organization (WHO) and United Nations (UN) has highlighted the need for better control of SARS-CoV-2 infections. However, developing novel virus-specific vaccines, monoclonal antibodies and antiviral drugs against SARS-CoV-2 can be time-consuming and costly. Convalescent sera and safe-in-man broad-spectrum antivirals (BSAAs) are readily available treatment options. Here, we developed a neutralization assay using SARS-CoV-2 strain and Vero-E6 cells. We identified the most potent sera from recovered patients for the treatment of SARS-CoV-2-infected patients. We also screened 136 safe-in-man broad-spectrum antivirals against the SARS-CoV-2 infection in Vero-E6 cells and identified nelfinavir, salinomycin, amodiaquine, obatoclax, emetine and homoharringtonine. We found that a combination of orally available virus-directed nelfinavir and host-directed amodiaquine exhibited the highest synergy. Finally, we developed a website to disseminate the knowledge on available and emerging treatments of COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Neutralization Tests/methods , Pneumonia, Viral/drug therapy , Amodiaquine/pharmacology , Animals , COVID-19 , Caco-2 Cells , Cell Line, Tumor , Chlorocebus aethiops , Coronavirus Infections/therapy , Drug Therapy, Combination , Emetine/pharmacology , HEK293 Cells , HT29 Cells , Homoharringtonine/pharmacology , Humans , Immune Sera/immunology , Immunization, Passive/methods , Indoles , Nelfinavir/pharmacology , Pandemics , Pyrans/pharmacology , Pyrroles/pharmacology , SARS-CoV-2 , Vero Cells
10.
Int J Infect Dis ; 93: 268-276, 2020 Apr.
Article in English | MEDLINE | ID: covidwho-1172

ABSTRACT

Viral diseases are one of the leading causes of morbidity and mortality in the world. Virus-specific vaccines and antiviral drugs are the most powerful tools to combat viral diseases. However, broad-spectrum antiviral agents (BSAAs, i.e. compounds targeting viruses belonging to two or more viral families) could provide additional protection of the general population from emerging and re-emerging viral diseases, reinforcing the arsenal of available antiviral options. Here, we review discovery and development of BSAAs and summarize the information on 120 safe-in-man agents in a freely accessible database (https://drugvirus.info/). Future and ongoing pre-clinical and clinical studies will increase the number of BSAAs, expand the spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections as well as co-infections.


Subject(s)
Antiviral Agents , Drug Development , Drug Discovery , Animals , Antiviral Agents/therapeutic use , Humans , Virus Diseases/drug therapy
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