Lecture 8 Antivirals Flashcards
What is the most severe constraint limiting the use of antivirals?
toxicity to the mammalian cell
Antivirals are said to have ____ ____ toxicity
poor selective
antivirals should interfere with a virus specific function that is either ____________ or _________
unique to the virus;
similar host function is much less susceptible to the drug
antivirals also can interfere with a _____ function necessary for viral _____
cellular; replication
Effective antiviral drugs have a therapeutic index of ___ to ___
100, 1000
All antivirals are viro___
static
2 examples of drugs that inhibit entry into host cells:
maraviroc; enfurvitide
____ is a CCR5 receptor antagonist
maraviroc
What is noncompetitive resistance and what drug is it especially associated with?
HIV uses drug bound form of CCR5 as the co-receptor; resistance in maraviroc
Maraviroc dosage should be modified when used with drugs that inhibit or stimulate
CYPA3
____ works by inhibiting the function of the gp41 transmembrane glyoprotein
enfuvirtide
Enfuvritide has low _____ _______, so it is mainly used for salvage therapy
oral availability
Viral uncounting is pH ____ in the endosomes/lysosomes but is pH _____ when fusing with the plasma membrane
dependent; independent
Example of drugs that inhibit viral uncoating:
amantidine and rimantidine
Raltegravir, dolutegravir, and elvitegravir work by inhibiting ______
integrase
Advantages of dolutegravir (2nd gen) or raltegravir):
- limited _______ profile
- prolonged serum ____
- minimal metabolization via ____, decreasing drug drug interactions
cross-resistance;
half-life;
CYP450
There is lesser risk of transmitting ____ ____ among individuals when using integrase inhibitors
drug resistance
Viral mutations leading to resistance against dolutegravir also diminish HIV ____ and ____ enzymatic activity
replication; integrase
Antivirals that inhibit polymerases are selective because:
1.
2.
virus uses its own enzyme to activate the drug;
viral polymerases are much more sensitive to drug than host
The fact that thydmidine kinase can phosphorylate the nucleoside analogs permits administration of the drug in a nonphosphorylated form that has what advantage over phosphorylated forms?
enters cell much more easily
2 examples of drugs that inhibit mRNA transcription and processing
ribavirin, interferon
____ nonspecifically inhibit protein translation
interferons
_____ helps the spread of influenza by removing scialic acid from the surface of infected cells so viruses can escape
neuraminidase (sialidase)
_____ is an inhibitor of viral neuraminidase
zanamivir
____ blocks gycosylation of viral hemagglutinin in the golgi apparatus, preventing viral maturation
nitazoxanide–used in influenza
Amantadine/rimantadine are _____ blockers that inhibit __
M2 channel, uncoating
Amantadine is thought to inhibit ____ in the _____
acidifcation, golgi
Amantadine also acts on maturation of the influenza _____ glycoprotein, decreasing the ____ potential of virus progreny
HA; infective
_____ was the first liscensed antiviral, but was too toxic for systemic use due to lack of ____
Idoxuridine; specificity
Idoxuridine and trifluridine are used ____ to treat herpes ____ and primary _______
topically; keratitis; keratoconjunctivitis
Ribavirin is a ____ nucleoside analog that inhibits ____ formation on mRNA
purine;
5’ cap
Ribavirin is used to treat _____ as an aerosol and hepatitis ____; limited use due to toxicity
RSV; C
1st step of acyclovir activation:
phosphorylation by HSV thymidine kinase
Acyclovir is a ___ analog that competes with _____
guanosine, dGTP
Triphosphate acyclovir acts as a _____ because it does not have a ____ group
chain terminator;
3’ OH
____ toxicity may be seen with high doses of acyclovir
renal
After receiving its 2nd and 3rd P’s from ____ enzymes, acyclovir binds to _____ and inhibits it
cellular
DNA polymerase
_____ has better _____ _____ than acyclovir because it is a prodrug
valacyclovir; oral bioavailability
____ is a monophosphate nucleoTIDE analog that is used to treat acyclovir resistant HSV
cidofovir
___ is a helicase primase inhibitor that is also used in treatment of HSV
pritelivir
Azidothymidine/zidovudine (AZT) is a ______
nucleoside reverse transcriptase inhibitor
AZT must be _____ to become active. It binds ______, aka reverse transcriptase
phosphoryalted; RNA dependent DNA polymerase
Side effects of AZT: ______ surpression, _____ disturbances.
bone marrow; GI
There is an increased risk of side effects with AZT if used with drugs that interact with the _______ pathway such as _____
glucuronyl transferase; aspirin/acetaminophen
Lamivudine is a ___ analog and is a _____
cytosine; NRTI
What else does lamivudine treat?
Hep B
_____ is a nucleTide reverse transcripase inhibitor used to treat HIV
tenofovir
sofosbuvir is used in ____ treatment by interfering with the _____ ____
Hep C; NS5B RNA polymerase
NNRTIs such as efravirenz work by ______ inhibting RT. ___ develops rapidly
physically; resistance
Dasabuvir (NNRTI) is used in treatment of _____ by acting as an analog of _______
Hep C; nonstructural NS5B
Favipiravir is used in treatment of _____ and inhibits the viral ______
influenza A and B; polymerase heterotrimer
Favipiravir is a ____ analogue that inhibits viral polymerase _____. It has a high barrier for _____
nucleobase; PB1; drug resistance
Protease inhibitors end in _____
navir
Protease inhibitors bind to the active site of _____ protease of HIV
aspartyl
_____ is used to increase the efficiency of other protease inhibitors of HIV
ritonavir
____ is given with ritonavir as a salvage option for patients with resistance to other protease inhibitors
tipranavir
____ and ____ are examples of direct acting antivirals that treat HEP c
telaprevir, bocepravir
Telaprevir and bocepravir target _____ in treatment of HCV
NS3/4A non structural protein
HCV drugs are beginning to focus on Direct acting antivirals that permit increased sustained virologic ____, _____, and shortened ______ of treatment
response, tolerability, duration
_____ is an example of an inhibitor of viral complexes
daclatasvir
Daclatasvir treats ____ by inhibiting ______ protein
HCV, NS5A nonstructural
inhibitors of ____ end in asvir
viral complexes
New directions for antivirals include:
- targeting the viral _____ complex (ie CMV),
- targeting virus-host interaction,
- iSAVE-based gene therapeutics that use genetically modifed host ____
- baseline ____ testing
- taking into account _____ genotypes
terminase;
T-Cells;
resistance;
viral
alpha and beta interferons prevent viral infection of noninfected cells by binding to _____ _____; also enhance expression of _____
surface receptors; MHC
_____ interferon enhances the specific T cell mediated immune response
gamma
Why were interferons hoped to be so effective?
act at several levels of the viral cycle
What is an example of Pre-exposure prophylaxis for HIV?
Truvada (emtricitabine/tenofovir disoproxil fumarate)
