Conserved cis-acting sequences of RNA viruses as antiviral drug targets

Table of Contents

• The need for antiviral drugs
• The ideal antiviral drug
• The viral target, and drug resistance
• High mutation rates of RNA viruses
• Conserved features of viruses as ideal drug targets
• Conserved features of RNA viruses
• Conserved cis-acting sequences of RNA viruses
• Mechanisms for maintaining cis-acting sequence conservation
• Inhibiting the recognition of the cis-acting sequences

• Mutation During Replication
  • The probability of producing a perfect copy of the master sequence
  • The probability of producing a copy with 1 specific mutation
  • The probability of producing a copy with E specific mutations
• Effect of mutations on the population of progeny genomes
  • The abundance of individual sequences in the progeny population
  • The number of mutants in each error class
  • The abundance of each error class in the population
• The sequence diversity of the population
  • The total diversity available for selection is enormous!
  • An analogy may be useful, to help visualize the quasispecies

• Substrates for selection
• The adaptive landscape
  • The topography of the adaptive landscape
  • Coverage of local sequence space by real populations
• Traversing the selective landscape
• Environmental change
• Maintenance of the 'wildtype' sequence
• Bottlenecks, random drift, and Muller's ratchet
  • Recovery of fitness and the re-emergence of the 'wildtype' virus
• Adjacent and Contingent Sequence Space

• Cis-acting sequences are remarkably well conserved
• Compilation of conserved cis-acting sequences of RNA viruses
  • Picornaviridae: Enteroviruses, Rhinoviruses, Apthoviruses, Cardioviruses, Hepatitis A viruses
  • Togaviridae: Alphaviruses, Rubella virus
  • Caliciviridae: Human and animal caliciviruses
  • Flaviviridae: Flavivirus, Pestiviruses, Hepaciviruses
  • Nodaviridae: Nodaviruses
  • (unassigned): Benyviruses
  • Rhabdoviridae: Vesiculoviruses, Lyssaviruses, Novirhabdoviruses
  • Paramyxoviridae: Respiroviruses (Paramyxoviruses), Morbilliviruses, Rubulaviruses, Pneumoviruses
  • Filoviridae: Marburg, Ebola viruses
  • Orthomyxoviridae: Influenza A, B, and C viruses; Thogoto virus
  • Arenaviridae: Lassa Fever, lymphocytic choriomeningitis, Junin, Tacaribe, Pichinde viruses
  • Bunyaviridae: Bunyaviruses, Hantaviruses, Nairoviruses, Phleboviruses, Tospoviruses
  • Reoviridae: Reoviruses, Orbiviruses, Rotaviruses, Coltivirus
• Evolution of the cis-acting sequences

• The model: Coupled evolution
• Predictions of the model
  • The conserved 'wildtype' sequence is optimal
  • The recognition of the cis-acting sequence is functionally conserved
• Implications for antiviral drug design

• Attack the cis-acting sequence itself
• Attack the cognate proteins that recognize the cis-acting sequence
  • Is the cognate protein(s) of viral or host origin?