15 Antiviral agents Flashcards
why is it harder to develop selectively toxic antiviral drugs compared to antibiotics
viruses are intracellular parasites and rely on many of the host cells mechanism and machinery for replication, so most drugs target replication and damage the host cell too
however, when it was discovered that viruses carry their own enzymes, this became a target for selective antiviral treatment
what was the first successful antiviral drug to be developed without damaging host cell
aciclovir
aciclovir is an analogue of
deoxyguanosine
how does aciclovir work (main thing it does)
incorporated into a growing DNA chain, acts as a DNA chain terminator
highly effective but only works against viruses which are able to phosphorylate it, herpes family, only HSV and VZV
mechanism of action in aciclovir (steps)
aciclovir is inactive, it has to be triphosphorylated
the key to selectivity is that an enzyme derived from virus phosphorylates aciclovir first (thymidine kinase), host cells cannot phosphorylate it, so nontoxic to normal cells
2nd and 3rd phosphate groups are added by cellular enzymes to produce aciclovir triphosphate
then competes with deoxyguanosine triphosphate for incorporation into a growing DNA chain and terminates it
give 3 ways aciclovir is selectively toxic
1 only activated in virally active cells
2 becomes concentrated in virally active cells (when cell has virus which can phosphorylate, as aciclovir gains a phosphate group, the intracellular concentration of free aciclovir will drop, more will diffuse into cell)
3 final molecule will bind better and inhibit viral DNA polymerase better than cellular DNA polymerase
describe 3 ways aciclovir resistance occurs
1 if virus doesn’t have thymidine kinase pre-treatment, but without this enzyme they’re non-pathogenic
2 mutations in thymidine kinase genes during therapy so can’t phosphorylate, but also non-pathogenic
3 mutations in DNA polymerase so the final molecule can’t bind to it and act as a chain terminator, clinical problem
what is valaciclovir formed of
ester of valine and aciclovir
benefits of valaciclovir compared to aciclovir
better orally absorbed and available in blood stream, easier in terms of dosage regimes
describe penciclovir, what is it administered as and is it better than aciclovir
also an analogue of deoxyguanosine, works in same way as aciclovir but not a chain terminator, although still an inhibitor with a higher affinity for viral DNA polymerase than cellular
administered as famciclovir (esterified)
aciclovir and penciclovir are equal in clinical trials
describe the presence of genital herpes in men
recurs as clusters of vesicular lesions on an erythematous base, usually on penis shaft or glans
aciclovir in genital herpes- prophylaxis
frequent, severe, atypical genital HSV= continuous aciclovir therapy to suppress recurrences
start on high dose and drop down to minimal dose so they remain disease free
usually leads to reversion to pre-therapy state, long-term therapy
what’s a dendritic ulcer and complications involved
shallow ulcer on cornea, complication of herpes
usually resolves without leaving much damage, but problem is when the virus goes latent in the nerves which supply the cornea
each time it recurs= more potent inflammatory response
can lead to complete opacity of cornea, commonest infection cause of blindness in UK
would give aciclovir but most damage is by host’s immune response, so would give steroids, should be managed by ophthalmologist
describe complication of herpes in the brain
infection of the brain= encephalitis
replication of herpes in brain substance
aciclovir can be life saving, ASAP for survival and survival without brain damage, use IV if suspicious before confirmed diagnosis to minimise brain damage
3 complications with HSV
dendritic ulcer in eye
encephalitis in brain
eczema herpeticum- complication in patients with eczema, spread across non-intact skin, can gain access to peripheral blood stream and organs (have supplies of aciclovir at home if have eczema and herpes in case of recurrence)
what viruses are sensitive to aciclovir
herpes simplex virus and varicella zoster virus
HSV and VZV
what does VZV cause
chicken pox (primary varicella), varicella, shingles, herpes zoster
commonest life threatening complication of VZV
varicella pneumonia= primary viral pneumonia with virus in the lungs
intensive care
give IV aciclovir
what increases the risk of getting chicken pox pneumonia
pregnancy, more likely to get it and die from it
aciclovir isn’t licensed for this situation but use in special circumstances
what is ganciclovir and why was it made
halfway between aciclovir and penciclovir, analogue of deoxyguanosine.
one herpes virus where antiviral agent is needed is CMV (cytomegalovirus), but it doesn’t make the required enzyme so resistant to a and p, so g was made
needs to be phosphorylated to ganciclovir triphosphate -inhibits viral DNA polymerase
active against all herpes viruses
problems with ganciclovir
poorly orally absorbed- so now have valine ester valganciclovir
host cells can also phosphorylate it, so toxic to normal cells especially in bone marrow
what is cidofovir and why was it made
problem with aciclovir is not many viruses can phosphorylate it, so tried to make a version where the first phosphorylation is already done-> cidofovir
has first phosphate group already on cell, takes away one layer of selectivity, rely on fact that the active molecule will have greater affinity for viral DNA polymerase than host
toxic side effects
non-viral dependent phosphorylation
advantage of cidofovir
broadens spectrum of antiviral action, theoretically inhibit any viral DNA polymerase, not just herpes family
analogue of cidofovir
adefovir- licensed for treatment of hep B
3 drugs used for cytomegalovirus
ganciclovir, cidofovir, foscarnet
describe foscarnet
use in CMV not a nucleoside analogue active form- requires no phosphorylation inhibits viral DNA polymerase where it forms phosphodiester linkages in DNA chain poor oral availability so give IV nephrotoxic
CMV is an important pathogen in which 2 main groups of immunosuppressed patients
HIV and transplant recipients
what is ribavirin
nucleoside analogue
inhibits viral DNA synthesis
broad spectrum of activity
not sure on mode of action- might interfere with MRNA access onto ribosome
3 real uses of ribavirin
1 RSV- respiratory syncytial virus which is the commonest cause of lower respiratory tract infection in young babies, inhaled, reduces high mortality
2 Lassa fever- viral hemorrhagic fever
3 mostly used in chronic hep C infection with interferon, not cured on it’s own
name 2 uncoating inhibitors
amantadine and rimantadine (analogue of a)
describe amantadine
inhibits uncoating of influenza A virus, blocks ion channel which would normally cause uncoating
effective but poorly tolerated because of CNS stimulation and resistance rapidly emerges, so no longer recommended
agitated, hallucinations, affects sleep, single point mutation
name 2 neuraminidase inhibitors
zanamavir (inhaled)
oseltamivir (oral)
what is neuraminidase
viral glycoprotein, viruses use to attach to receptors on target cells
describe normal neuraminidase activity
the virus that buds out of the cell becomes a virion
if neuraminidase didn’t exist, the haemagglutin on the virion would simply bind back to sialic acid on host cell and get stuck on the surface of the cell, so virus evolved neuraminidase on it’s surface to cleave from sialic acid residues and allow it to get away and infect new cells
how do neuraminidase inhibitors work
neuraminidase can no longer cleave the haemagglutin on virion from the sialic acid on host cell, so the virion isn’t released
works against 16 influenza neuraminidase
