Targeting viral genome synthesis as broad-spectrum approach against RNA virus infections

Abstract

Zoonotic spillover, i.e. pathogen transmission from animal to human, has repeatedly introduced RNA viruses into the human population. In some cases, where these viruses were then efficiently transmitted between humans, they caused large disease outbreaks such as the 1918 flu pandemic or, more recently, outbreaks of Ebola and Coronavirus disease. These examples demonstrate that RNA viruses pose an immense burden on individual and public health with outbreaks threatening the economy and social cohesion within and across borders. And while emerging RNA viruses are introduced more frequently as human activities increasingly disrupt wild-life eco-systems, therapeutic or preventative medicines satisfying the “one drug-multiple bugs”-aim are unavailable. As one central aspect of preparedness efforts, this review digs into the development of broadly acting antivirals via targeting viral genome synthesis with host- or virus-directed drugs centering around nucleotides, the genomes’ universal building blocks. Following the first strategy, selected examples of host de novo nucleotide synthesis inhibitors are presented that ultimately interfere with viral nucleic acid synthesis, with ribavirin being the most prominent and widely used example. For directly targeting the viral polymerase, nucleoside and nucleotide analogues (NNAs) have long been at the core of antiviral drug development and this review illustrates different molecular strategies by which NNAs inhibit viral infection. Highlighting well-known as well as recent, clinically promising compounds, structural features and mechanistic details that may confer broad-spectrum activity are discussed. The final part addresses limitations of NNAs for clinical development such as low efficacy or mitochondrial toxicity and illustrates strategies to overcome these.

Anti-SARS-CoV-2 Strategies and the Potential Role of miRNA in the Assessment of COVID-19 Morbidity, Recurrence, and Therapy

“…These two agents disrupt viral replication. Potential methods of interference with viral replication can be direct RdRp inhibition that interrupts RNA replication (such as HCV inhibitors) and the application of nucleoside analogs causing premature termination of RNA replication and indirectly inhibiting the activity of RdRp [37] (panel B). Oxidative stress inhibitors may also be useful in treating COVID-19.…”

Pyrimidine biosynthesis inhibitors synergize with nucleoside analogs to block SARS-CoV-2 infection

“…SARS-CoV-2 is a coronavirus, which is a family of single stranded positive sense RNA viruses, at least seven of which infect humans. RNA viruses including coronaviruses replicate using a virally encoded RNA-dependent RNA polymerase (RdRp), and nucleoside analogs which are misincorporated by the RdRp into the growing viral RNA chain are a large class of approved direct acting antivirals ( 3 ). Depending on the analog, misincorporation can lead to chain termination or mutagenesis ultimately inhibiting viral replication ( 4 ).…”

Therapeutic Inhibitory Activities of N‐Hydroxy Derived Cytidines: A Patent Overview

“…Hence it was accomplished as a lead compound towards developing novel antiviral structures (Figure 27). [64] …”

“…Hence it was accomplished as a lead compound towards developing novel antiviral structures (Figure 27). [64] β-D-N 4 -hydroxycytidine (NHC) scaffolds were evaluated as inhibitors for orally bioactive broad-spectrum antiviral drugs against SARS-CoV-2 in human airway epithelial (HAE) cell ChemistrySelect cultures associated through in vitro and in vivo using Remdesivir as standard drug. [65] Compound 37 (NHC) exhibited high antiviral activity against recombinant Middle East respiratory syndrome coronavirus (MERS-CoV) expressing nanoluciferase with IC 50 values of 0.15 μM, with no significantly examined cytotoxicity (Figure 28).…”