Exam 4 lecture 3 Flashcards
What are the two types of herpes simplex viruses?
HSV-1
- causes oral herpes, can cause genital herpes
60% of adults in US are seropositive
Reactivates on face or lips
HSV-2
common cause of genital herpes, but can cause oral herpes
16% of adults in US (more common in women and african americans)
reactivates in genital areas
Varicella zoster virus (VZV) causes what diseases
Caused shingles and chicken pox. reactivates later in life
How is shingles caused? WHat complication can it cause? Transmission?
Virus migrates to ganglia in area of infection. Rash and blisters scab over.
Causes postherpetic neuralgia (PHN)
Shingles is not transmitted, but virus can cause chicken pox
How is shingles prevented
CDC recommends 2 doses of shingrix separated by 2-6 months forall immunocompetent adults 50 and older
What is CMV? When is it an issue?
cytomegalovirus affects 80% of adults, most have no sx. Infection occurs in immunocompromised people (AIDS)
If infection occurs during fetal development, may cause congenital abdormalities, most infants are not affected.
name anti herpesvirus agents
Acyclovir
Valacyclovir
cidofovir
Foscarnet
Penciclovir
Ganciclovir
Valganciclovir
What type of drugs are valacyclovir and acyclovir
prodrugs
MOA of acyclovir?
selectively accumulates in infected cells.
Results in higher concentration in infected cells
Is incorporated in DNA chain as a chain terminator
How is acyclovir activated?
requires 3 phosphorylations to form active acyclovir triphosphate
what type of inhibitor is acyclovir? How?
Competitive inhibitor of viral DNA polymerase
Competes with dGTP
summary of acyclovir
Acyclovir is incorporated into DNA
Acts as a chain terminator
acyclovir spectrum of activity
active against HSV-1, 2 and VZV
reduced activity against cytomegalovirus
How can resistance occur with acyclovir
- mutations in viral thymidine kinase (phosphorylation does not occur)
- mutations in viral DNA polymerase
Resistant common in immuocompromised pts
DIfference between valacyclovir and acyclovir structurally
Allows for oral bioavailability higher that acyclovir. Rapidly converted to acyclovir in liver.
How is valacyclovir transpoorted
by intestinal amino acid transporters
Relationship of famciclovir and penciclovir
Famciclovir is a prodrug of penciclovir.
Famciclovir converted to penciclovir by 1st pass metabolism
How are famciclovir and penciclovir activated? MOA?
Activated by viral and cellular kinases
Competitive inhibitor of viral DNA polymerase
short chain terminator (allows limited DNA chain elongation)
Do famciclovir and penciclovir cause immediate chaintermination?
NO, allow for short chain elongation
How does resistance occur in famciclovir and penciclovir
Viral kinase mutants confer cross resistance to penciclovir and acyclovir
compare penciclovir and acyclovir in terms of affinity and efficacy for HSV TK (Thymidine kinase)? Why?
Penciclovir has higher affinity for HSV TK than acyclovir
Levels of penciclovir triphosphate in infected cells are much higher than levels of acyclovir triphosphate
Penciclovir triphosphate is more stable than acyclovir triphosphate in HSV infected cells
HSV DNA polymerase have higher affinity for acycyclovir triphosphate than for penciclovir triphosphate
Net effect- both drugs equal antiviral properties
clinical use of famciclovir and penciclovir
oral- Herpes (acute, or genital or primary)
Topical- herpes
MOA of ganciclovir
MOA same as penciclovir
Compare ganciclovir to acyclovir
ganciclovir better substrate for cytomegalovirus kinase than acyclovir
100X better
Toxicity of ganciclovir more severe than acyclovir
clinical use of ganciclovir
IV, PO and IO implants can be used to treat CMV retinitis
Oral ganciclovir can be used for CMV prophylaxis
toxicity of ganciclovir
myelosuppression
- neutropenia
- thrombocytopenia
What is the resistance mechanism for ganciclovir
Due to mutations in CMV kinase
for ganciclovir, are mutations cross resistant with cidofovir? Foscarnet?
Mutations in kinase are not cross resistant to cidofovir or foscarnet
Mutations in DNA polymerase may confer resistance to cidofovir or foscarnet (less frequent)
Compare valganciclovir and ganciclovir? use?
Valganciclovir is more orally bioavailable. Rapidly hydrolyzed to ganciclovir in intestine/liver.
used to treat CMV retinitis in AIDS pts
MOA of foscarnet? Does it require phosphyrylation? (exam)
Inhibits viral DNA polymerase by blocking pyrophosphate binding site of the viral DNA polymerase (remember), (traps DNA polymerase in closed formation)
Does not require phosphorylation for activity (1st drug so far)
What does the foscarnet ability to block pyrophosphate binding site of DNA polymerase lead to
Inhibits cleavage of pyrophosphate from dNTPs
How is foscarnet administered? main use?
only administered IV
CMV retinitis (equivalent to ganciclovir)
toxicity of foscarnet
Renal insufficiency
Hypo/hyper phosphatemia/calcemia
Resistance MOA of foscarnet? cross resistance?
Mutations in DNA pol or HIV reverse transcriptase
Resistant are cross resistant to ganciclovir
is foscarnet still effective against cidofovir resistant CMV
yes
What type of analog is cidofovir? How is it phosphorylated (EXAM)
cytosine
Phosphorylated by cellular kinases
Phosphonate cannot be cleaved by cellular esterases- catabolically stable
SOA of cidofovir?
CMV, HSV-1, 2, VZV, adenovirus, poxvirus, polyomavirus and HPV
MOA of cidofovir? Does it require activation by viral kinases
Competitive inhibitor by CMV pol and chain terminator.
Does not require activation by viral kinases
adverse effect and clinical use of cidofovir
dose dependent nephrotoxicity
CMV retinitis
What is letermovir used for?
Prophylaxis of CMV infection and disease in adult allogenic hematiopoietic stem cell transplant (HSCT) pts who have CMV
what is unique about letermovir
non nucleoside
Highly specific for CMV (no activity against herpes virus members)
What type of virus in influenza
Negative stranded RNA virus, enveloped
can infect humans, birds, pigs, horses
What are the three types of influenza? Describe them
3 types, A< B, C
A infects humans and many different animals (ducks, chickens, pigs, whales, horses and seals)
B widely circulates in humans
C causes mild disease
A and b cause epidemics nearly every winter
What are the two influenza A subtypes? How many of each exist?
Hemagglutin (H)
Neuraminidase (N)
Both exposed proteins (N is enzyme) if N is inhibited, we stop ability to of virus to leave infected cell and spread
16H genes and 9 N genes
how do neuraminidase inhibitors work?
Inhibitors block neuraminidase activity and blocks viral enzyme activity, reduces spread
What is the influenza neuraminidase used for?
Essential for virus replication
- cleaves glycolytic bonds between terminal sialic acids and adjacent sugars
Facilitates virus dissemination
Name neuraminidase inhibitors
Sialic acid
Zanamavir
DANA
Oseltamivir
MOA of oseltamivir
prodrug, converted to active form by liver esterase
metabolite inhibits neuraminidase.
Less effective against B
therapeutic use of ostltamivir
need to initiate within 48 h of first symptoms of influenza to see effect
describe mechanism of resistance of oseltamivir
Resistance is associated with mutations in the active site of neuraminidase
resistance develops easier with oseltamivir than zanamivir
MOA od zanamivir
Same as oseltamivir, binds and inhibits neuraminidase activity, inflenza a and b, but more for A
ot is an oral inhaler
Excretion of zanamavir
Excreted unchanged by kidneys (not a prodrug like oseltamivir)
Toxicity of zanamivir
bronchospasms have been seen, not recommended in pts with COPD or asthma
MOA of paeramivir
Transition state analog of sialic acid, IV drug
baloxavir marboxil MOA, indication and adverse effects
MOA- inhibits viral cap- snatching (blocks transcription)
Clinical indication- influenza within 48 hrs of sx
adverse effects- diarrhea, bronchitis
What type of virus is Hep C? Transmission?
small, positive stranded RNA virus, causes chronic liver infection
Contaminated blood/needle sharing
What can Hep C lead to?
Chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC)
what is a part of the Hep C life cycle that can be targeted by meds
Hep C forms a large poly protein that is cleaved by viral proteases.
What does virus form after viral protease cleaves protein
forms replication complex where polymerase resides to replicate RNA genome.
why do interferons work against HCV
interferons induce synthesis of cellular proteins, have antiviral effects
What analog is ribavirin? How is it activated?
Guanosine analog
phosphorylated by cellular kinases to triphosphate form
SOA of ribavirin
Influenza A and B
Hep A, B, C
Herpes
Measles
Hantavirus
Lassa fever virus
MOA of ribavirin
Inhibits inosine monophosphate dehydrogenase (IMPDH)- reduces GTP levels.
direct inhibition of viral RNA polymerase and incorporation into viral RNA leading to error and catastrophe
clinical use of ribavirin
Combo therapy for hep C
HCV protease inhibitors MOA
Target the HCV protease NS3, block cleavage of the HCV polyprotein
form reversible covalent bonds
what are the 2 second gen HCV protease inhibitors
P1-P3 substarate analogs- Simeprevir and paritaprevir (non covalent inhibitors)
P2-P4 sibstarate analogs- Grazoprevir, voxilaprevir and glecaprevir (covalent)
How does resistance occur in HCV protease inhibitors
Mutations in NS3 active site
What is the RNA polymerase in hep c called? What targets it
NS5B
sofosbuvir targets it
sofosbuvir MOA
Incorporated in viral RNA chain. Causes chain termination.
name a non nucleoside RNA polymerase inhibitor for Hep C
Dasabuvir
how many binding sites does NS5B hav?
5 known binding sites (1 catalytic and 4 allosteric sites). Dasasbuvir can bind allosteric sites
MOA of dasabuvir
Binds to palm I site of HCV RNA polymerase. prevents conformational changes.
blocks neucleotide incorporation into viral RNA
nameNS5A inhibitors
Ledipasvir (1st gen)
Elbasvir (1st gen)
Daclatasvir (2nd gen)
Velpatasvir (2nd gen)
Pibrentasvir (2nd gen)
NS5A inhibitors MOA
Bind tightly to NS5A, inhibits both viral RNA replication and assembly or release of infectious viral particles
how does resistance to HCV NS5A inhibitors occur
Mutations occur in 1st 100 amino acids
how to remember NS3 protease inhibitors? NS5A inhibitors? NS5B inhibitors
NS3- -previr
NS5A inhibitors- -asvir
NS5B inhibitors-buvir
blackbox warning for HCV direct acting antivirals (DAA)
Hep B reactivation has occured in pts co infected with Hep C while undergoing tx with DAAs for HCV
DAAs used without interferon have resulted in fulminant hepatitis, hepatic failure and death
what can Hep B lead to
Can cause chronic liver infections that lead to cirrhosis and hepatocellular carcinoma
name anti HBV drugs
Tenofovir
Entecavir
lamivudine
all pro drugs
name drugs for SARS COV 2
remdisivir
Nirmatrelvir
Molnupiravir
Remdesivir SOA, MOA and ROA
broad spec antivral
Prodrug that is biotransformed to ribonucleotide anakog that inhibit viral RNA polymerase
IV
nirmatrelvir MOA
protease inhibitor.
molnupiravir MOA
prodrug that serves as polymerase inhibitor and chain terminator
