Jack of All Trades: Broad cellular functions of RSAD2/Viperin could provide novel strategies for antiviral therapeutics

Jack of All Trades: Broad cellular functions of RSAD2/Viperin could provide novel strategies for antiviral therapeutics

Upon infecting human host cells, viruses hijack the cellular replication machineries to assemble additional virus particles and propagate infection, leading to illness. One important component for ensuring replication is the availability of nucleotides (ATP, CTP, GTP, and UTP), which are the building blocks of DNA and RNA. However, the activity of DNA or RNA polymerase can be inhibited by a variation of these nucleotides (also known as nucleotide analogues) that are missing the 3’-hydroxy group. Currently, multiple nucleotide analogues either have been utilised or are in development stages as antiviral or anticancer therapeutics.

In a series of recent publications, Dr. Kourosh Honarmand Ebrahimi, a postdoctoral fellow at the Department of Chemistry in collaboration with Professor William James’s lab at the Dunn School, reported possible antiviral functions for a 3’-hydroxy group-lacking CTP analogue, ddhCTP. ddhCTP is generated by an interferon-inducible protein RSAD2/Viperin, a key enzyme of the innate immune response. Besides catalysing CTP-to-ddhCTP conversion, RSAD2/Viperin has previously been shown to play a role in various cellular processes. Thus, how RSAD/Viperin and the generation of ddhCTP exert antiviral functions have remained elusive.

In their current work, Dr. Ebrahimi and colleagues showed that the conversion of CTP to ddhCTP depletes available cellular concentration of CTP and interferes with the functions of mitochondria. To investigate how RSAD/Viperin could alter broad cellular processes during viral infection, Dr. Ebrahimi and colleagues utilised human induced pluripotent stem cells (hiPSC)-derived macrophages that lack the expression of RSAD/Viperin protein. They showed that ddhCTP inhibits NAD+-dependent activity of several enzymes, possibly by direct competition of NAD+ binding to these important metabolic enzymes.  

Overall, Dr. Ebrahimi and colleagues propose that disruption of NAD+-dependent cellular activity by RSAD2/Viperin-catalysed ddhCTP during pro-inflammatory cues, such as virus infection, could have wide range of downstream effects, protective or suicidal, depending on cell types, in order to restrict the pathogen threats. These studies open up new avenues for exploring novel antiviral drug targets.

The three relevant papers can be found here:

  1. https://febs.onlinelibrary.wiley.com/doi/full/10.1002/1873-3468.13778
  2. https://febs.onlinelibrary.wiley.com/doi/full/10.1002/1873-3468.13761
  3. https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10.1002/cbic.201900776

 

Derek Xu