Anti-Virals 2: Anti-influenza agents Flashcards
Virus structure (flu) - RNA
Hemagglutinin – functions in attachment of the virus to a host cell.
Neuraminidase – facilitates release of de novo virus particles from host cell
Replication cycle of RNA encoded viruses
The M2 protein of influenza virus allows an influx of hydrogen ions into the virion interior, which in turn promotes dissociation of the RNP (ribonuclear protein)
segments and release into the cytoplasm (uncoating)
Influenza virus mRNA synthesis requires a primer
cleared from cellular mRNA and used by the viral
RNAp complex.
The neuraminidase inhibitors
zanamivir and oseltamivir specifically inhibit release
of progeny virus. Small capitals indicate virus proteins.
• rubella (+)
• rhabdoviruses (rabies) (-)
• picornaviruses (+) (poliomyelitis, meningitis, colds,
hepatitis A)
• flaviviruses (hepatitis C) (+)
• orthomyxoviruses (-) (influenza A, B, C)
• paramyxoviruses (measles, mumps) (-)
• coronaviruses (colds, SARS, MERS, COVID-19) (+)
• arenaviruses (Lassa fever) (-)
what are these?
•Examples of RNA viruses
name anti-influenza agents (4)
- Amantadine, rimantadine
- Ribavirin
- Oseltamivir (Tamiflu®) (Roche)
- Zanamivir (Relenza®) (GSK)
Influenza
- Type A, B, and C
- Type A, B – seasonal flu, pandemic
- The surface proteins are usually changing, resulting in the need for seasonal vaccination
- H1N1 Swine flu 2009; Spanish flu 1918
Amantadine, Rimantadine
MOA?
which channel?
• Both inhibit the proton channel function of the
influenza A M2 matrix protein, which is required for
uncoating (decapsidation) of the viral genomic material
M2 channel: It enables hydrogen ions to enter the viral particle (virion) from the endosome, thus lowering the pH inside of the virus, which causes dissociation of
the viral matrix protein M1 from the ribonucleoprotein RNP
- Drug binding to an open channel blocks it
- Drug binding to a closed channel stabilizes it
Amantadine, Rimantadine
resistance
• mutations in the amino acid sequence of
the M2 proton channel can confer resistance
to these drugs
• High resistance has been noted in influenza
A/H3N2 from 2005-2007
viral resistance to these drugs require diff therapeutic strategies
Viral neuraminidase
role?
• Neuraminidase catalyzes the release of virions from the surface of infected cells, by cleaving off sialic acid residues from the cell receptor
for influenza virus.
• By blocking the activity of neuraminidase, these drugs preventing the spreading of the infection to new cells
Oseltamivir (Tamiflu®)
Structural similarities of drugs (false substrates)
- Active against amantadine-resistance influenza (A & B).
- Inhibits viral neuraminidase (106 more specific than human), prevents release of new viruses from cell.
- Treatment is associated with ~ half of the risk of subsequent hospitalization in adults
- Can be used as prophylactic treatment (75 mg once daily); 70-90% effective in both un/immunized
- Resistance: single amino acid mutations in neuraminidase enzyme
- resistance levels in adults ~ 1%, but higher resistance levels in children ~18%
- resistant strains are usually less virulent
activation from carboxylate
Zanamivir (Relenza®)
Structural similarities of drugs (false substrates)
• inhibits viral neuraminidase and thus causes viral
aggregation at the cell surface and reduced spread of
virus
• Influenza A & B
• N-acetylneuraminic acid (sialic acid) analogue, inhibits
influenza viral neuraminidase
• Protective in household transmission; early treatment
(10 mg 2x for 5 d) shortens illness resolution time.
• Can be effective in cases of oseltamivir resistance
Peramivir
- Approved since 2014, but used under emergency use in the 2009 H1N1 pandemic.
- I.V. administration, one dose within 2 days of symptoms
Xofluza
- Approved last fall (FDA)
- Baloxavir marboxil
- Novel mechanism “first-in-class” compound
- Inhibits mRNA replication of influenza virus
- Inhibits endonuclease function of viral PA polymerase
- About same effect as Tamiflu (reduces duration of symptoms by about 1.5 days)
- But need just one dose
• Rapidly hydrolyzed to S-033447 (baloxavir)
“Snatch-and-grab” inhibitor
xofluza (baloxavir acid)
- transc of viral mRNA involves capturing and cleaving first 10-20 nucleotides of 5’ capped host mRNAs to be used as primers in viral RNA synthesis
- newly developed inhibitor of viral endonuclease responsible for cap-snatching shows therapeutic efficacy for flu treatment
Coronavirus
3 viruses
- 2002 SARS-CoV (China) - Bats
- 2012 MERS (S. Arabia) – Bats/Camels
- 2019 SARS-CoV-2 (China) - Bats
The “Spike” is covered with sugars, which is thought to camouflage it from the immune system
Binding of virus spike to angiotensin converting enzyme 2 (ACE2) on the cell surface
Remdesivir
- Originally designed for Ebola, RSV, etc.
- Remdesivir-PPP inhibits RNA dependent RNA pol of MERS*
- Can cause chain termination (but not immediately, so still needs study)
Remdesivir activation
As usual, the triphosphate is the active metabolite
More complicated prodrug - needs at least 2 steps of chopping
3 steps of phosphorylation
