Active Components of Commonly Prescribed Medicines Affect Influenza A Virus-Host Cell Interaction : A Pilot Study

Background: Every year, millions of people are hospitalized and thousands die from influenza A virus (FLUAV) infection. Most cases of hospitalizations and death occur among the elderly. Many of these elderly patients are reliant on medical treatment of underlying chronic diseases, such as arthritis, diabetes, and hypertension. We hypothesized that the commonly prescribed medicines for treatment of underlying chronic diseases can affect host responses to FLUAV infection and thus contribute to the morbidity and mortality associated with influenza. Therefore, the aim of this study was to examine whether commonly prescribed medicines could affect host responses to virus infection in vitro. Methods: We first identified 45 active compounds from a list of commonly prescribed medicines. Then, we constructed a drug-target interaction network and identified the potential implication of these interactions for FLUAV-host cell interplay. Finally, we tested the effect of 45 drugs on the viability, transcription, and metabolism of mock- and FLUAV-infected human retinal pigment epithelial (RPE) cells. Results: In silico drug-target interaction analysis revealed that drugs such as atorvastatin, candesartan, and hydroxocobalamin could target and modulate FLUAV-host cell interaction. In vitro experiments showed that at non-cytotoxic concentrations, these compounds affected the transcription and metabolism of FLUAV- and mock-infected cells. Conclusion: Many commonly prescribed drugs were found to modulate FLUAV-host cell interactions in silico and in vitro and could therefore affect their interplay in vivo, thus contributing to the morbidity and mortality of patients with influenza virus infections.Peer reviewe

Seven classes of antiviral agents

The viral epidemics and pandemics have stimulated the development of known and the discovery of novel antiviral agents. About a hundred mono- and combination antiviral drugs have been already approved, whereas thousands are in development. Here, we briefly reviewed 7 classes of antiviral agents: neutralizing antibodies, neutralizing recombinant soluble human receptors, antiviral CRISPR/Cas systems, interferons, antiviral peptides, antiviral nucleic acid polymers, and antiviral small molecules. Interferons and some small molecules alone or in combinations possess broad-spectrum antiviral activity, which could be beneficial for treatment of emerging and re-emerging viral infections.Peer reviewe

Publisher Correction: Breaking the speed limit with multimode fast scanning of DNA by Endonuclease V.

Ahmadi A, Rosnes I, Blicher P, et al. Publisher Correction: Breaking the speed limit with multimode fast scanning of DNA by Endonuclease V. Nature communications. 2019;10(1): 1991.The original version of this Article was updated shortly after publication to add a link to the Peer Review file, which was inadvertently omitted. The Peer Review file is available to download as a Supplementary File from the HTML version of the Article

Screening of FDA-Approved Drugs Using a MERS-CoV Clinical Isolate from South Korea Identifies Potential Therapeutic Options for COVID-19

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.Peer reviewe

Mono- and combinational drug therapies for global viral pandemic preparedness

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.Peer reviewe

Nafamostat-Interferon-alpha Combination Suppresses SARS-CoV-2 Infection In Vitro and In Vivo by Cooperatively Targeting Host TMPRSS2

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 (IFN alpha) 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 IFN alpha 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.Peer reviewe

Culture density at time of helper phage infection predicts ssDNA yield.

<p>Scatter plot of large-scale (200 mL) ssDNA preparations infected at various MOI greater than one, following anion-exchange column purification. Black line represents the local polynomial regression (loess) curve and grey area the 95% confidence interval, as determined by R software.</p

Second strand synthesis yields.

<p>(A) Box plots of second strand syntheses yields by starting amount of ssDNA indicate scalable and reliable yields. (B) Box plots comparing yields of lesion-free versus lesion-containing (8-oxoG, 5-OHU, or DHU) constructs, per 40 μg of ssDNA, or as expected per 40 μg of ssDNA if actual starting ssDNA amount was less (20–30 μg). Similar yields are obtained for lesion-free and lesion-containing constructs. Whiskers extend 1.5 times the interquartile range from the 25^th and 75^th percentiles, which are indicated by box limits. Center lines indicate the medians and circles represent the values for individual preparations. Determined by R software.</p

Lesion-containing construct quality controls.

<p>(A) Schematic of the Fpg nicking assay. Fpg cleaves damages, such as 8-oxoG and 5-OHU, leaving a single-strand break, converting the construct from covalently closed (cc) to nicked form. (B) Lesion structures. (C) Representative images of Fpg and Nth nicked T5 exonuclease-treated lesion-containing and lesion-free control constructs. Fpg cleaves 8-oxoG, 5-OHU, and DHU, nicking the lesion-containing constructs almost entirely, but not the lesion-free controls, and Nth cleaves DHU.</p

Optimization of the DH12S <i>E</i>. <i>coli</i> culture and phage infection conditions for phagemid ssDNA yield.

<p>(A) Schematic of the experimental design for the systematic analysis of the effect of culture OD₆₀₀ at phage infection and multiplicity of infection (MOI) on ssDNA yield. Cultures were infected at varying OD₆₀₀ or MOI and ssDNA yields were determined by proteinase K digestion of precipitated phage particles, followed by agarose gel electrophoresis. (B) OD₆₀₀ at phage infection predicts ssDNA yield. (C) Increasing MOI beyond that which is necessary to infect all cells does not improve ssDNA yield. (D) Gel quantification of two biological replicates, each containing three technical replicates, of cultures infected at varying OD₆₀₀ and identical MOI. (E) Quantification of ssDNA yields from cultures infected at varying MOI. Averages include two biological replicates, each containing three technical replicates. Error bars indicate the standard deviation. (F) Cultures that otherwise produce high yields of phagemid ssDNA, infected at MOI > 2.5 or 10, do not yield ssDNA when diluted 2 hours following phage-infection.</p