Flashcards in Antimicrobial Agents- Antivirals Deck (56):
An ideal antiviral would target all major pathogenic viruses by doing either what to things? do these exist?
1. either targeting a highly conserved viral target or targeting a cellular protein that is critical for virus replication
Review the following common viral targets?
viral mRNA synthesis
translation viral mRNA
replication viral genome
maturation virus particle
budding, release new virus
What is the goal of antivirals against HIV?
reduce virus loads as low as possible, increase CD4 T cells counts
How does maraviroc act?
small molecule inhibitor- binds CCR5 allosterically preventing HIV gp120/CCR5
Does maraviroc enhance CD4 T cell counts even in individuals who carry CXCR4- utilizing HIV? how does resistance set in?
2. changes in HIV gp120
How does enfuvirtide work? what is the problem with this?
1. C peptide mimic that binds N peptide on HIV gp41- preventing fusion
2. expensive to synthesize and causes local inflammation
What are the two different kinds of RT inhibitors?
1. competitive substrates for nucleosides/tides
2. small molecule inhibitor of RT activity
How do NRTIs work…what do they lack?
analog- lacking 3 hydroxyl group causing DNA chain termination
All NRTIs require what?
phosphorylation by cellular enzymes to the triphosphate form
What is the difference between NRTIs and NtRTIs?
NtRTIs have one phosphate group on the pro-drug
What makes NRTIs and NtTRIs so effective? how does virus gain resistance?
1. cellular polymerases have proof reading activity whereas HIV does not
2. increased ability to exclude NTRI or remove the analog
What are the 3 NRTIs we need to know?
Which NRTI is a guanosine analog and not a cytosine analog?
What is the one NtRTI we need to know? what is a major side effect issue with this drug
competes with other drugs for kidney tubule secretion
Do we often find combinations of NtRTIs and NRTIs?
How do non-nucleoside RT inhibitors (small molecule inhibitors) work?
1. binds to an allosteric site on RT, hydrophobic pocket near catalytic domain- decreases mobility of RT--> inhibits polymerase
Do non-nucleoside and nucleoside RT inhibitors use the same domain?
No- distinctly different domains are responsible for the antiviral activity
What are the 2NNRTIs?
What is dolutegravir?
T-F--integrase inhibitors work by joining viral 5'DNA ends?
HIV protease inhibitors block what? how?
1. blocks the maturation of the virus particle
2. derived from natural peptidic substrates of HIV-1 protease and bind active site
What are the side effects of ritonavir/ saquinavir - protease inhibitor?
lipodystrophy-central adipose tissue
[numerous effects supposedly, but that's the only one listed]
What are 2 protease inhibitors?
ritonavir (blocks 3A4)
[mentions atazanair in the lecture but not on the drug sheet]
HAART regimens usually include 3 drugs---what are they in general terms?
usually 2 nucleoside RT inhibitors and either a protease inhibitor or a non-nucleoside RTI or an integrate inhibitor
What can antivirals for HIV also be used for? which one has been most successful?
microbicides, post exposure prophylaxis, maternal-fetal transmission
tenofovir for microbocide
Ganciclovir can be used for what 2 herpes?
Foscarnet can be used for which herpes viruses? 4
CMV, EBC, VZV, HSV 1 &2
Famciclovir, valacyclovir and acyclovir are used for what herpes?
HSV and VZV
What is acyclovir and valacyclovir activated by? how do they work?
1. viral nucleoside kinase
2. incorporate in elongation of DNA and terminate production of new genome
When do we use acyclovir and valacyclovir for prophylaxis?
BMT and organ transplant
Between acyclovir and valacyclovir, which one provides more sustained and higher levels in the blood?
The whole family of HSV inhibitors elevate what?
HIV NRTIs---amounts should be adjusted.
T-F--famciclovir is an acyclic guanine derivative has a different mose of action do to 3' OH group?
true- still cause chain termination
T-F--cidofovir is an acyclic nucleoside phosphonate derivative of adenine?
What is cidovir activated by?
cellular kinases and thus does not need virus encoded TK- MAINTAIN ACTIVITY FOR STRAINS WITHOUT TK
Is cidofovir a competitive inhibitor of the viral DNA polymerase or a chain terminator?
mainly a polymerase inhibitor, but can act as a chain terminator
How does foscarnet work?
binds directly to pyrophosphate binding sites of HSV DNA polymerase--NONCOMPETITIVE (100x more that host cells)
Docosanol is what?
A saturated fatty alcohol that is approved as a topical cream
Usually we use ganciclovir IV for CMV severe cases. It is more effective for HSV and VZV, but why don't we use it?
It is toxic--> granulocytopenia and thrombocytopenia
What is fomivirsen-
antisense RNA against CMV that can be used against CMV retinitis in immunocompromised individuals
What is amantadine and rimantadine?
Influenza viral uncoating inhibitor
What is zanamivir and oseltamivir?
influenza neuraminidase inhibitor
How does amantadine work?
binds M2 blocks acidification--Influenza A only
Does amantadine need to be used quickly?
yes within 48 hours of first symptoms
T-F--most circulating influenza strains are resistant to amantadine? what else is it used for?
Palivizumab is used to treat who?
infants under 2 with cardiac or pulmonary disease prophylactically for RSV
Hospitalized acutely ill infants with RSV are treated with what?
ribavirin- nucleoside analog
In what ways does ribavirin work? 3
1- inhibit inosine monophosphate dehydrogenase depleting guanosine triphosphate
2- base pair with cytidine or uridine--> mutations
3- shifts CD4 T cells from Th2 to Th1
Combination therapy with nucleoside RT inhibitors and what is best for Hep B?
lamivudine is what?
specific HBV nucleoside analogue reverse transcriptase inhibitor
What is simeprevir?
HepC protease inhibiotr
What is sofosbubir?
Hep C nucleoside inhibitor
What is a flavivirus, plus strand, that infects about 3% of the world
What is wrong with ribavirin and interfering alpha 2a treatment for chronic hep C?
50% of US cases are resistant-- [ribavirin is oral and INFa is injected.]
What do we use simeprevir with?
ribavirin and IFNalpha 2a