Broad-Spectrum Antiviral Strategies and Nucleoside Analogues

The emergence or re-emergence of viruses with epidemic and/or pandemic potential, such as Ebola, Zika, Middle East Respiratory Syndrome (MERS-CoV), Severe Acute Respiratory Syndrome Coronavirus 1 and 2 (SARS and SARS-CoV-2) viruses, or new strains of influenza represents significant human health threats due to the absence of available treatments. Vaccines represent a key answer to control these viruses. However, in the case of a public health emergency, vaccine development, safety, and partial efficacy concerns may hinder their prompt deployment. Thus, developing broad-spectrum antiviral molecules for a fast response is essential to face an outbreak crisis as well as for bioweapon countermeasures. So far, broad-spectrum antivirals include two main categories: the family of drugs targeting the host-cell machinery essential for virus infection and replication, and the family of drugs directly targeting viruses. Among the molecules directly targeting viruses, nucleoside analogues form an essential class of broad-spectrum antiviral drugs. In this review, we will discuss the interest for broad-spectrum antiviral strategies and their limitations, with an emphasis on virus-targeted, broad-spectrum, antiviral nucleoside analogues and their mechanisms of action

Utilisation de l'isocyanate de chlorosulfonyle dans la synthèse de composés d'intérêt biologique (les acides N-(O-alkylsulfamoyl) -et N-(N-alkylsulfamoyl)-phosphoramidiques)

MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Titer reduction assay dose-response.

<p>Titer reduction assay dose-response.</p

Active nucleobases and their corresponding nucleosides.

<p>Dose-response results for selected compounds evaluated in DENV replicon cells. Doses were performed in triplicate and each dose-response experiment was performed independently at least twice. Mean values plus standard deviation for results from each compound are shown. Mycophenolic acid served as a non-nucleobase/nucleoside control inhibitor. TTI is the tissue culture therapeutic index (CC₅₀ / EC₅₀). N/A = not available.</p

Nucleobases and corresponding nucleosides display potent antiviral activities against dengue virus possibly through viral lethal mutagenesis

<div><p>Dengue virus affects millions of people worldwide each year. To date, there is no drug for the treatment of dengue-associated disease. Nucleosides are effective antivirals and work by inhibiting the accurate replication of the viral genome. Nucleobases offer a cheaper alternative to nucleosides for broad antiviral applications. Metabolic activation of nucleobases involves condensation with 5-phosphoribosyl-1-pyrophosphate to give the corresponding nucleoside-5’-monophosphate. This could provide an alternative to phosphorylation of a nucleoside, a step that is often rate limiting and inefficient in activation of nucleosides. We evaluated more than 30 nucleobases and corresponding nucleosides for their antiviral activity against dengue virus. Five nucleobases and two nucleosides were found to induce potent antiviral effects not previously described. Our studies further revealed that nucleobases were usually more active with a better tissue culture therapeutic index than their corresponding nucleosides. The development of viral lethal mutagenesis, an antiviral approach that takes into account the quasispecies behavior of RNA viruses, represents an exciting prospect not yet studied in the context of dengue replication. Passage of the virus in the presence of the nucleobase <b>3a</b> (T-1105) and corresponding nucleoside <b>3b</b> (T-1106), favipiravir derivatives, induced an increase in apparent mutations, indicating lethal mutagenesis as a possible antiviral mechanism. A more concerted and widespread screening of nucleobase libraries is a very promising approach to identify dengue virus inhibitors including those that may act as viral mutagens.</p></div

Titer reduction assay dose-response.

<p>Titer reduction assay dose-response.</p

Potential base pairing of nucleoside triphosphate forms of 3a and 3b.

<p>Once converted to the active nucleoside triphosphate forms, mutagens <b>3a</b> and <b>3b</b> may adopt different conformations due to the rotation of the amide bond allowing these compounds to mimic GTP and base pair with C or mimic ATP and base pair with U.</p

The number of mutations per sequence clone.

<p><b>A</b>. Virus was passaged in cells treated with compounds indicated. The prM/E region from viral RNA was amplified using RT-PCR, ligated into a vector and approximately 35–50 independent clones were chosen for each drug treatment at indicated passage. The nucleotide sequence of the DENV region was determined using standard Sanger sequencing methods for each clone. Thin black horizontal bar indicates the mean number of mutations per clone and the vertical bars indicate the 95% confidence intervals. Four asterisks signify p < 0.0001. P values determined using a two-tailed Mann-Whitney U test. <b>B</b>. The DMSO passage data from <b>A</b> graphed separately. P = passage and D = DMSO.</p

Sequence analysis of DENV passages.

<p>Sequence analysis of DENV passages.</p