Exam 4 - Antivirals (Medchem-Stahelin) Flashcards
There are ___#___ classes of viruses
6
what are the 6 different classes of viruses?
double stranded DNA single stranded DNA single stranded RNA -- negative sense single stranded RNA -- positive sense retroviruses
Viruses Facts:
Obligate _________
intracellular parasites
Viruses Facts:
small or large genomes
small
Viruses Facts:
Must use ________ to replicate
host cell machinery
Viruses Facts:
Inhibit cellular pathways to promote replication —
what are 3 common pathways that are inhibited??
cell death (apoptosis) interferon tumor suppression (p53)
Some viruses are surrounded by lipids?
If covered by lipids they are called _____
if no lipid layer they are called _____
enveloped
non enveloped….
what are some examples of enveloped viruses
HIV
influenza
herpes
what are some examples of non-enveloped viruses
picornavirus
adenovirus
General Virus Life cycle steps?
steps 1 - 8
- viral attachment/entry
- penetration
- uncoating
- nucleic acid synthesis
- integration / transcription
- viral protein synthesis
- packaging/assembly
- viral release
what drug class will block viral release from the cell?
neuraminidase
HIV Fusion/Entry:
HIV _______ binds to _____ on target cell
gp120 (on HIV cell) binds to CD4 (on target cell)
HIV Fusion/Entry:
A conformational change will occur where a region of GP120 is exposed… the exposed region binds to the __________ receptor
cytokine
HIV Fusion/Entry:
The exposed region binds to a cytokine receptor will be ______ or ____ depending on the strain of HIV
CCR5 or CXCR4
_________ and ________ are HIV entry and fusion inhibitors
Enfuviritide
Maraviroc
Enfuviritide MOA?
binds to GP41 ON HIV and blocks the GP41 conformation
HIV fusion/entry inhibitor
Maraviroc MOA
binds to HUMAN CCR5 and blocks GP120 binding
Enfuviritide binds to ________ cells
Maraviroc binds to ________ cells
Enfuv: binds to HIV cells
Mara: binds to human cells
Maraviroc:
can only be used in patients with HIV strains that _______
utilize CCR5
Enfuvirtide is only active against HIV ______
1
what are the 3 jobs of Reverse Transcriptase (RT)?
RNA dependent DNA Pol
Ribonuclease H
DNA-Dependent DNA Pol
Reverse transcriptase copies the ______ strand of RNA to make the _____ strand of DNA
plus strand RNA to minus strand DNA
NRTIs interfere with ____________ synthesis
1st and 2nd strand DNA synthesis
NRTIs MOA
they are nucloeside analogs that lack the 3’ OH =
- competitive inhibitor of reverse transcriptase
- DNA chain terminator (inhibits elongation)
T or F:
All NRTIs need to be activated/they are prodrugs
TRUE!
need to be activated by kinases
What activation step do NRTIs need?
need activated by kinases / need to get to a triphosphate (PO4- need to be added)
what NRTI has the longest half life
Tenofovir DISOPROXIL FUMURATE aka a prodrug…
problems with tenofovir disoproxil fumarate (TDF)?
TFV is eliminated by the kidney = if kidney issues, acute renal failure is more likely
and overall there is a larger reduction in bone mineral density compared to other NRTIs
what is a different prodrug option for TFV?
TAF
(tenofovir alafenamide)
activated by a diff pathways/ fewer side effects
what enzyme is used to activate TAF
CatA (cathepsin A)
T or F:
The same kinase is used to add the 3 phosphates
FALSE! different kinases for each addition!1
activated NRTIs compete with what 4 things to be incorporated into the growing DNA chain made by RT
4 things: dATP, dCTP, dGTP, and dTTP
NRTIs have a higher affinity for______ than __________
higher affinity for HIV RT than cellular DNA pol
Tenofovir requires __#___ phosphorylation steps
2
Resistance to HIV Drugs:
why do mutations happen so quickly?
HIV pol is error prone
RT inhibitors are unable to suppress viral replication
Large amount of viruses are present
Resistance to HIV Drugs:
Rate at which mutations appear is _______ related to the serum ______
inversely related
serum drug concentration
If there a drug has a ______ genetic barrier it is easy for a virus to become resistant
low
if there a drug has a ____ genetic barrier it is hard for a virus to become resistant
high
what are the 2 kinds of resistance to NRTIs
Discriminatory mutations
or
Excision mutations
Explain discriminatory mutations towards NRTIs
helps the RT distinguish between normal dNTPs and NRTIs
Explain excision mutations against NRTIs
promote removal of NRTIs after thye have been incorporated into the growing chain
Single NRTI therapy has a ______ genetic barrier
low
ADEs of NRTIs?
Mitochondrial toxicity
Lipoatrophy
Abacavir Hypersensitivity (black box)
Why does mitochondrial toxicity happen with NRTIs
NRTIs are selective for HIV RT over DNA pol alpha and beta but NOT gamma
(aka some NRTIs will inhibit DNA pol-gamma)
what effects are seen with mitochondrial toxicity
!![anemia granulocytopenia myopathy peripheral neuropathy pancreatitis]!! lactic acidosis hepatic steatosis
what is lipoatrophy
loss of body fat
what does Abacavir hypersensitivity look like?
Malaise
dizziness
headache
GI disturbances — STOP IMMEDIATELY if any of these
what allele should be tested for with Abacavir use
HLA-B 5701
What are two of the recommended combo NRTI therapies
Tenofovir/Emtracitabine
or
Abacavir/Lamivudine
(emtracitabine and lamivudine are interchangable)
what NRTI therapies are not recommended
monotherapy
dual NRTI therapy (if no other antivirals)
3 NRTI (because too much toxicity)
MOA of NNRTIs
bind to what?
block what?
bind directly to the site of RT
block polymerization
NRTIs or NNRTIs compete with nucleotides for binding (aka noncompetitive inhibitors)
NRTIs do compete
T or F:
NNRTIs need to be phosphorylated
false!!
NNRTIs do NOT need to be phosphorylated
(NRTIs doooo)
2nd Gen NNRTIs
are designed to be inherently ________ which allows them to ________
inherently FLEXIBLE
allows them to bind in multiple orientations(can bind to mutants)
ADEs of NNRTIs
rash
drug drug interactions
Nevirapine – hepatotoxicity (SJS rash)
Efavirenz – neuropsychiatric, teratogenic in primates
Specific ADEs of Nevirapine
it is a NNRTI
and it causes hepatotoxicity and SJS rash
Specific ADE of Efavirenz
it is a NNRTI
neuropsychiatric
teratogenic in primates
Metabolism of NNRTIs
All metabolized by ________
CYP3A4
NNRTI Facts:
They do or do not require activation
do not
NNRTI Facts:
Do or not compete with dNTPs
do not
NNRTI Facts:
Do or do not get incorporated into DNA
do not
NNRTI Facts:
Do or do not bind to cellular DNA pol
do not
NNRTI Facts:
A NNRTI mutation does or does not cause NRTI resistance
does not
Integrase Enzyme works to do what?
insert HIV DNA into host cell DNA
Integrase inserts HIV DNA into host cell DNA in what 2 steps?
3’ processing
Strand Transfer
MOA of Integrase Inhibitors:
works by blocking what?
binds to what?
blocks the strand transfer step
binds to/chelates to metal ions and stabilizes enzyme-DNA complex
Integrase uses ______ to catalyze insertion
divalent metal ions
which INI has the highest genetic barrier (compared to other INIs)
Dolutegravir
what drug is used with Elvitegravir to boost its concentrations
Cobicistat
why is cobicistat given with Elvitegravir?
Cobi inhibits CYP3A4 = inhibits metabolism of Elvitegravir = higher elvitegravir levels
Does dolutegravir have higher or lower barrier of resistance
higher barrier
HIV Protease is an ______ protease
aka has a _____ in the active site
aspartic protease
has aspartic acid in active site
HIV protease inhibitors are _______mimetics
and can of what 2 types?
transition state mimetics
could be peptidomimetic or nonpeptide compounds
HIV Proteases job is what?
- cut itself free and the cuts 4 other enzymes free from the long precursor
- peptide bond cleavage via hydrolysis reaction reaction
how do Protease inhibitors work?
- they have a replaced amide bond with a non cleavable linkage
- causes a conformation change/closes it
All protease inhibitors except for _____ are consider peptidomimetics
tipranavir
Metabolism of Protease Inhibitors:
Are they affected by CYP?
yes!
all are substrates and some are inhibitors
what protease inhibitor is the most potent inhibitor of CYP enzymes
Ritonavir
_______ is a protease inhibitor if given at low doses is used to increase serum concentrations of other antivirals
Ritonavir
What are the two unique features of darunavir?
makes extensive hydrogen bonds with protease backbone
inhibits HIV protease dimerization
Protease inhibitors:
have the lowest or highest genetic barrier compared to other antivirals
highest
ADEs of Protease inhibitors?
Hyperlipidemia Insulin resistance/diabetes lipodystrophy(changes in body fat) Elevated liver function tests possible increase bleeding risk in hemophiliacs drug-drug interactions
Herpes Virus:
(small or large)
(single or double) stranded
(RNA or DNA) virus
LARGE
DOUBLE
DNA
Herpes Virus infections can be in what 2 forms of infection?
lytic (producing new virions)
latent (dormant)
HSV-1 or HSV-2:
which one normally causes oral herpes
1
HSV-1 or HSV-2:
which one normally causes genital herpes
2
CMV (cytomegalovirus) usually not a problem unless what….
unless infection happens during fetal development
or
if immunocompromised pt
what are some anti-herpesvirus agents
acyclovir valacyclovir cidofovir foscarnet penciclvir ganciclovir valganciclovir...
Acyclovir MOA?
competitive inhibitor of _______
competes with ____
is an (reversible or irreversible) inhibitor
competitive inhibitor of viral DNA pol (lower concentration needed for VIRAL DNA pol than host DNA pol)
competes with dGTP
is an irreversible inhibitor
Acyclovir:
requires phosphorylation?
yes!! 3 phosphorylation events
Acyclovir:
is incorporated into _______ and is a _____ terminator
DNA;
chain
two main resistance mechanisms to acyclovir?
mutations in viral thymidine kinase
or
mutations viral DNA pol
relation of valacyclovir to acyclovir?
valacyclovir is L-valyl ester of acycylovir…
converted to acyclovir by esterases in the intestines/liver
Famciclovir and Penciclovir relation?
famciclovir is a prodrug of penciclovir
activated by 1st pass metab of intestine and liver
MOA of famiciclovir/penciclovir (how is it different than acyclovir)
Fam and pen are competitive inhibitors of viral DNA pol BUT they do NOT cause immediate chain termination (they allow for short chain elongation)
Penciclovir or Acyclovir:
which one has higher affinity for HSV TK (thymydine kinase)
penciclovir
Penciclovir or Acyclovir:
which has higher affinity for HSV DNA pol
acycolovir
Penciclovir or Acyclovir:
which one is more stable in HSV infected cells
penciclovir
T or F: Topical penciclovir and famciclovir are great for topical herpes infections
FALSE: pencic is good but famcic needs 1st pass metab – aka famcic not used topically)
Ganciclovir is structurally similar and same MOA as ________
but Ganciclovir is a better substrate for ______ than others
same MOA as penciclovir
better substrate for cytomegalovirus kinase
Is toxicity in ganciclovir or acyclovir worse?
ganciclovir toxicity is worse
Ganciclovir or Valganciclovir:
which one has good bioavailability?
which one has bad bioavailability?
Gancic: BAD bioavail
Valgan: GOOD bioavail
Foscarnet Facts:
Needs or does not need phosphorylation for activity
does NOT need
Foscarnet Facts:
what kind of compound is it
inorganic pyrophosphate compound
MOA of Foscarnet:
It blocks ________ binding site of the viral ______
and inhibits cleavage of ________ from _______
blocks pyrophosphate binding site
of viral DNA pol;
cleavage of pyrophosphate from dNTPs
Foscarnet Facts:
What is it used for?
CMV (like ganciclovir)
Foscarnet Toxicities?
renal insufficiency (RENAL ADJUST) phosphate levels (hypo or hyper) calcium levels (hypo or hyper) headaches
Foscarnet MOA:
inhibits what enzymes?
viral DNA pol
RNA pol
HIV RT
Cidofovir:
acyclic nucleoside phosphonate analog of ______
cytosine
MOA of Letermovir mechanism
inhibits terminase complex
(normally herpes virus DNA replicates through rolling circle mechanism and individual genomes need to be cut out by the terminase complex)
influenza virus
(positive or negative) strand (DNA or RNA) virus
negative RNA virus
3 types of influenza virus?
A,B,C
Influenza Viruses: A, B or C
___ will infect humans and many different animals
A
Influenza Viruses: A, B or C
___ widely circulates in ONLY humans
B
Influenza Viruses: A, B or C
___ causes a very mild disease
C
Influenza Viruses: A, B or C
____ and ____ cause epidemics nearly every winter
A and B
Influenza A Subtypes are divided into two gene types: what are the two gene types?
H and N
H - hemagglutinin
N - Neuraminidase
what are the two ways influenza viruses change?
Antigenic drift
or
Antigenic shift
Antigenic Drift or Shift:
small changes to the virus
drift
Antigenic Drift or Shift:
major abrupt change to the virus
shift
Amantadine and Rimantandine:
inhibits __________ by targeting the ___ protein of influenza ____
inhibits penetration into host cells
by targeting M2 protein of influenza A
ADEs of Amantadine?
GI intolerance
CNS effects
(worse in older people – over 60 years of age)
influenza virus neuraminidase:
essential for virus _______
is located in the virus _______
replication
membrane
influenza virus neuraminidase:
works to cleave the glycolytic bonds b/w terminal _____ and adjacent sugars
sialic acids
influenza virus neuraminidase:
facilitates virus ________
______ binds to terminal sialic acid residues and _____ releases the virus
dissemination
HA (hemaglutinin)
NA (neuraminadase)
what drugs are neuraminidase inhibitors
zanamavir
oseltamivir
Oseltamivir:
Needs activated by liver – yes or no?
yes – it is a prodrug
Oseltamivir:
it is an effective inhibitor of _____
NA (neuraminidase)
Oseltamivir:
Effect depends on how soon therapy is started – need to initiate within _____ of first symptoms
48 hours
Dosage form for Oseltamivir and Zanamivir?
Oseltam: oral
Zanamivir: oral inhaler…
what is the newest neuraminidase inhibitor?
how is it administered?
it is a transition state analog of _____
Peramivir;
IV
sialic acid
HCV stands for?
Hepatic C Virus
Hepatic C Virus:
transmission via __________
Can cause what 3 things?
transmission via contaminated blood
can cause chronic hepatitis; liver cirrhosis, hepatocellular carcinoma
what does SVR stand for and what is its definition?
sustained virological response
HCV RNA is undetectable for 6 months after treatment
what is a common/nonspecific defense against viral infections
interferon
what are the HCV NS3 protease inhibitors
Telaprevir Boceprevir Paritaprevir Simeprevir Grazoprevir Voxilaprevir Glecaprevir
HCV Protease Inhibitors:
target the HCV protease _____
NS3
HCV Protease Inhibitors:
block the cleavage of the _____
HCV polyprotein
HCV Protease Inhibitors:
what drugs are the 2nd gen/P1-P3 substrate analogs
Simeprevir
Paritaprevir
HCV Protease Inhibitors:
what drugs are the 2nd gen/P2-P4 substrate analogs
Voxilaprevir
Glecaprevir
Grazoprevir
HCV RNA Polymerase inhibitors:
_____ is known as the HCV RNA pol
NS5B
what drug is a HCV RNA Polymerase inhibitor?
Sofosbuvir
Sofosbuvir:
does it need phosphorylated?
yes
Sofosbuvir Mechanism:
gets incorporate into _______ and causes ______
viral RNA chain (makes sense bc it is a RNA pol inhibitor..)
causes chain termination
what drugs are HCV NS5A inhibitors
Ombitasvir Ledipasvir Daclatasvir Velpatasvir (2nd gen) Pibrentasvir (2nd gen) (-ASVIR)
MOA of HCV NS5A inhibitors:
Inhibits both _______ and _______
viral RNA replication
and
assembly of release of infectious viral particles
what drugs are HCV NS5B inhibitors?
Sofosbuvir
Dasabuvir
(-BUVIR)
Blackbox warning for HCV direct acting antivirals (DAA)?
cases of fulminant hepatitis, hepatic failure, and death because of HBV (hepatic B virus) reactivation!!
The blackbox warning for HCV agents happens when the DAAs are _______
alone/NOT used with an interferon
Ways to decrease the HBV reactivation with HCV DAAs?
screen ALL pts for current or prior HBV infection
Monitor for HBV reactivation
talk to Drs who specialize in Hep B infections
– counsel patients to report side effects
What are signs of serious liver injury?
Yellow eyes or skin light colored stools fatigue/weakness loss of appetite N/V
