AV Flashcards
influenza Vaccine
best !
Zanamivir
Influenza neuroaminidase inhibitor
active drug
analogue of N-acetylneuraminic acid
used at early stages of infection
inhibit viral aggregation
release from cell
movement through upper respiratory tract
Oseltamivir
flu NA inhibitor ethyl ester pro-drug analogue of N-acetylneuraminic acid used at early stages of infection
inhibit viral aggregation
release from cell
movement through upper respiratory tract
Ribavirin
Hepatitis C
Flu
inhibits viral RNA dependent RNA polymerase
guanosine analogue take up
phosphorylated by cellular kinases to MP, DP, TP
MP = decrease GTP - inhibits inosine monophosphate dehydrogenase, hence DNA/RNA synthesis.
TP inhibits dGTP dependent 5’Cap formation on mRNA. mimick the cap to inhibit eIFE
bind the nucleotide binding site of viral RNA polymerase - inhibits initiation and elongation of viral mRNA
terogenic - causes haemolytic anaemia in up to 10% of patients - drug accumulation in RBCs
antiherpes
simplex + zoster active
all available ones target virally encoded DNA polymerase that replicate dsDNA genome.
viral DNA polymerase in same way as mammalian DNA polymerase.
Acyclovir
anti - herpes pro drug
specific purine analogue
lack cyclic sugar of 2’ deoxyguanosine
need viral thymidine kinase
then to acyclovir - TP by cellular enzymes
30 x more potent interaction with viral DNA Pol
competitive substrate
incoorperated and cause termination of DNA replication
uses of acyclovir
topicaly, oral, IV
cidofovir
herpes
pyrimidine analogue
nucleoside phosphonate analogue of cytosine
converted to diphosphoryl derivative by cellular enzymes
selectively inhibit DNA pol of CMV
incorporates itself into viral DNA
for CMV retinitis
MORE TOXIC - TOPICAL USE
side effects: nephrotoxicity, nausea, hair loss, vomiting etc
Trifluridine -
Idoxuridine
herpes
cytosine analogues
TOXIC
Trifluridine - does not require activation by TK , inhibits mammalian DNA pol too
Idoxuridine - inhibits viral DNA polymerase, requires viral TK
Foscarnet -
herpes
organic analogue of pyrophosphate
bind DNA Pol of CMV
selective but does not require IC metabolism
prevents cleavage of PPi from NTP during DNA synthesis
nephrotoxic proteinuria
IV
when acyclovir resistance occurs
however alterations in viral DNA pol may give resistance
HIV
two copies of single stranded RNA genome
reverse transcriptase - poor fidelity
aspartic acid protease - cleaves polyprotein ie Gag
RT inhibitors
HIV
non nucleoside reverse transcriptase inhibitors NNRTIs
NRTIs
nevirapine
NNRTI
HIV
used to prevent mother to child spread
bind hydrophobic pocket in the subdomain of p66 which is about 10 angstrom away from the active site (known as the NNRTI pocket)
AZT / zidovudine / azidothymidine
thymidine analogue
NRTI
lack 3’OH as replaced by non functional azido group (N3)
chain terminator
co - admin with hydroxyurea - decreases thymidine concentration - potentiates effects
Valyl ester - increases bioavailability - makes resemble peptide to utilise the non-selective peptide transporters in gut. ester bond cleaved in plasma ( used on other drugs too )
Amantadine
Rimantadine
FLU
targets M2 - prevent proton conductance.
2 mechanisms of binding
x-ray crystallography - bind to high affinity open state at low pH ( perhaps due to absence of pl bilayer)
NMR - show bind to low affinity closed state
prevent the acidification of intervir of virion needed for fusion of endosome and viral capsule membranes
Enfuvirtide
Fuzeon
HIV
peptide based fusion inhibitor hence uptake inhibitor
aa 643 - 678 section of gp41 - Hptad repeat 2
compete with viral HR2 for interaction with HR1
HR 1- 2 interactions allow coiled coils
HIV protease
aspartic acid protease
acid - base catalysis
has 2 intermediate states with exposed - OH groups
cleaves gag polypeptide to functional proteins
gag -> capsid, nuclear binding proteina, matrix proteins
saquinavir
HIV protease inibitor
transitional state analogue
has exposed -OH
higher affinity for enzyme than substrates
ritonavir nelfinavir indinavir amprenavir lopinavir
HIV protease inibitor
transitional state analogue
has exposed -OH
higher affinity for enzyme than substrates
interferons
+ adverse effects
secreted cytokines by cells after recognising viral infectio
activate protein kinase that inhibit ribosome initiation complex - PKR phosphorylates eIF2 which binds to eIF2B - make inactive
RNAase L - cleave viral dsRNA ( via OAS)
Mx protein - nucleoprotein sequestration
Adverse effects: acute flu like symptoms due to interleukin activation - fever headache fatigue impaired fertility bone marrow suppression neurotoxicity - confusion, seizures cardiotoxicity - arrhythmia
IFN alpha 2a
hepatitis B
can also use for herpes zoster and herpes simplex
IFN alpha 2B
hepatitis C
can also use for herpes zoster and herpes simplex
gamma interferons
less antiviral effects
mainly by NK cells and T cells
current drugs = virustatic
so successful antiviral therapy needs immunocompotence of host.
