anti-viral sg Flashcards
Herpes Viruses (chicken pox, AKA Varicella Zoster, VZV) CytomegalovirusCMV
hepatitis B
are these DNA, RNA, or retrovirus
DNA
Influenza A B C
Respiratory Syncytial Virus
Hepatitis C
are these DNA, RNA, or retrovirus
RNA
HIV-1 and HIV-2 aids
are these DNA, RNA, or retrovirus
retrovirus
general structure of a _
Nucleic Acid Core (DNA or RNA)
enzymes
Coat or Capside
Capsomere - protein subunits of the coat
some have lipoprotein envelope (carries antigens)
virus
General Considerations about Viral disease
- Viruses can attack human, animal, plant, and bacterial cells (bacteriophage)
- More than 400 species of viruses infect man, but only _ cause human disease
- Immunity against many viruses is _
- Different viruses can produce the same disease symptoms (e.g. upper respiratory tract)
- Same virus can produce different diseases depending on the host’s immunity and age.
- Viruses are small: Most viruses are 0.02-0.3 μm
- Viruses are not cells, they are obligate intracellular parasites
<50 cause human disease
immunity against viruses is lifelong
-Infection Process of virus
- _ (molecules on cell),
- Penetration & uncoating of genome,
- Replication/Transcription/Translation,
- Assembly, they have to reassemble
- Release,
- Secondary Infection
Adsorption
important receptor or HIV - CD4/CCR5 CXCR5
fuzeon CCR5 antagonist for HIV
Docosanol for HSV
3 types of viruses
DNA (Virus genome carried around in DNA form) Ex. Herpes
- Once penetrated and uncoated into _, viral DNA is transcripted into viral mRNA and replicated into more viral DNA
- viral mRNA goes to make proteins to get packaged with DNA to release (by host ribosomes)
nucleus
translated by host ribosomes for proteins, viral thymidine kinase, and viral DNA Pol. To replicate viral DNA -> assembly and release
3 types of viruses
Taken in by endocytosis, membrane fuses with nuclear membrane and uncoated by Amantidine and Rimantitidine.
RNA virus (flu)
- Single stranded viral RNA gets replicated in nucleus via cRNA to new Viral RNA
- Viral RNA can also be transcribed to Viral mRNA to make proteins
- Viral enzymes are released to create new viral enzymes and proteins for packaging and release (e.g. viral coat)
3 types of viruses
RNA retrovirus (Ex. HIV, carries genome around in RNA form, but goes through a DNA form inside the cell)
- genetic material exposed _
- Viral RNA matches up with cRNA to form double stranded DNA which gets taken into nucleus to replicate viral RNA, while other strands form viral mRNA for proteins, proteins and RNA packaged and released
outside of cell nucleus
- Attachment and penetration – uncoating in cytoplasm
- Viral genomic RNA + Reverse transcriptase -> cDNA-RNA complex
- Integrated into host cell DNA
- Replication -> new RNA and proteins -> release
_ immunity: B cell system, T Helper cells contact B cell holding correct antigen and MHC. TH cells produce cytokines to stimulate antibody production
B cell system, produce cytokines to stimulate antibody production
-Humoral immunity
_ immunity: destroys virus-infected cells,
secretes interferon – interferon activates cytotoxic T cells and other killer cells – induces _ to viruses
Cellular
induces resistance to viruses
_ take up and digest antigens to show antigens to helper cells
– surface with MHC -> production of IL-1
APC
protease inhibitors are most effective _ drug
HIV
_produce cytokines to promote immunity (IL-2),
contacts B cell holding the correct antigen w/ MHC
Helper T cell:
_activate cytotoxic t cell, natural killer cells and macrophages for virus-infected cells
, induces resistance of other cells to virus
Interferon:
_ binds antigen and can neutralize it, stem allows cells to recognize antigen to get swallowed by phagocyte
Antibodies:
General difficulties in viral chemotherapy
- Virus uses host cell machinery
- Narrow spectrum of antivirals
- Viral resistance
- Growth of virus may resume when drug is gone from system
- Virus is _
- Symptoms absent prior to viral large scale replication
- Immune system helps eliminate virus
- Lot of _ in viruses
intracellular
a lot of variability
passive or active immunity?
- With preformed Antiviral immunoglobulin
- Injected w/ antibodies to coat virus and induce phagocytosis
- Rapid onset of protection, lasts only months
- Good for immunodeficient patients, when rapid use needed
- Can be engineered antibodies or donor serum antibodies
passive
tx and prophylaxis
passive or active immunity
- Antigen administered to induce cellular/humoral immunity
- Takes time for protection, but stay immune for long time
- Ideally - > Prevents disease, low frequency needed, non toxic
- Creation of memory cells (T+B) when virus is presented later in life
- Used for prophylaxis
active
just prophylaxis
_ viral immunization
Passive
- ***Give to kids with RSV virus and can benefit them greatly - binds to F protein on virus surface and prevents viral entry into cells - RSV (RNA virus) most common cause of bronchitis and pneumonia in kids - 9x more deadly than flu - symptoms: edema, mucin, cell necrosis, obstruction
Pallvizumab
- Passive
- Binds to F protein on virus surface and prevents viral entry
- RSV (RNA virus) most common cause of bronchitis and pneumonia in kids
- 9x more deadly than flu
- symptoms: edema, mucin, cell necrosis, obstruction
INTERFERON
- produced by natural interferon producing cells
- express receptors that recognize viral DNA/RNA (TLR 7/9), viral intro creates type _ interferon
- produced by most normal cells
- activated by dsRNA, induce IFN production, intracellular double stranded receptors
- activates other interferon receptors, induces cell resistance
- Inhibits: penetration/uncoating, transcription/translation, viral glycosylation for maturation
- activates natural killer cells
TYPE 1
- Inhibits: penetration/uncoating, transcription/translation, viral glycosylation for maturation
- activates natural killer cells
INTERFERON
- Targets
- DNA: inhibit _
- RNA: Uncoating step, transcription via rna polymerase, attack viral enzymes
- Retro: adhesion, inhibit reverse transcription, inhibit integrase
DNA polymerase
Acyclovir
class?
-Metabolic activation by viral _ (acyclovir monophosphate)
competitive inhibition of viral DNA polymerase and incorporates it into DNA which causes chain termination
- Competes w/ dGTP, makes the triphosphate which inhibits DNA polymerase, terminates chain and inactivates polymerase
- Herpes virus mainly
- Metabolic activation – phosphorylated by Viral Thymidine Kinase > human kinase
Base analog
by thymidine kinase
DNA herpes virus drug
- activated by thymidine kinase just like acyclovir
- much less potent inhibition of DNA polymerase, accumulates higher levels, longer half life
- don’t cause chain termination but slow down polymerization
penciclovor
- Herpes – viral thymidine kinase performs 1st phosphorylation -> cellular kinases make di and triphosphates as in acyclovir
- Effective against CMV (UL97 Kinase phosphorylates drug first)
- U97 kinase phosphorylates drug first, followed by cellular kinases to make triphosphate version
- Competitively inhibits dGTP on DNA Polymerase – as well as inhibits elongation
ganciclovir
-Competitively inhibits dGTP on DNA Polymerase – as well as inhibits elongation
more effective against CMV
ganciclovir
-affects many DNA/RNA viruses. Effects GTP synthesis. **Inhibits production and use of RNA. Used to treat Hep C
ribavarin
– broad spectrum
-Affects many DNA/RNA viruses
-R-MP – inhibits GTP synthesis
– Inhibiting use of mRNA interfering with GTP capping of 5’ end
rna virus drug
FLU A
- Flu A only - Attacks M2 protein ion channel - Prevents uncoating (after entry)
amantadine
- Flu A/B
- Attacks/inhibits neuraminidase
- Doesn’t allow release of virus from cell membrane
- Attacks/inhibits neuraminidase
tamiflu
For Influenza, know the role of the M2 protein channel And the importance of neuraminic (or sialic) acid and neuraminidase
M2: allows genome release within cells (virus causes channels to open so genome can enter cytosol
-Neuraminic acid and neuraminidase: Neuraminidase cleaves acid from receptors disrupts binding to cell membrane and allows viral release
base analog
activated intracellularly to triphosphate by cellular enzymes
competes with dCTP to inhib reverse transcriptase
usted against both hep B and HIV
lamivudine
inhibs attachment of enveloped viruses to cells
active against DNA virsus HSV 1 and 2 6, CMV
RNA - Influenza and RSV
NOT ACTIVE AGAINST POLIOVIRUS, does not contain a lipid envelope
docosanol - abreva
blocks attachment step
topical cream 10% for oral HSV works if used within 12h of prodromal symptoms on face
Know the drug targets for _ Ledipasvir and associate it with a target 1. Protease 2. RNA polymerase 3. Non structural protein 5A (NS5A)
Hepatitis C »_space;»
-NS5A inhibitor (non structural protein)
hep C drug
Ledipasvir
HIV
_ attaches to CD4 T helper cells (CCR5 and CXCR4 receptors for adhesion)
- Reduces adhesion if targeted
GP 120:
HIV
_ critical for fusion of HIV w/ target cell membrane
- Reduces fusion w/cell membrane if targeted
GP 41:
You need to know there are 2 major families HIV-1 and 2
- Know the functions of _
- used for integration into host genome by viral integrase
LTR – Long Terminal repeat
- In host DNA, LTR recognized by HIV TAT protein and host transcription factors like NFkB – driving transcription of HIV genome in host DNA
HIV
CD4T numbers pattern: numbers start high then initial drop due to _,
followed by return to peak and plateau, until eventually slowly falling off, plateau from attacking host cells, final fall allows for infections
cytotoxic T cells
Generalizations
- No cure
- Contagious
- Treated AIDS patient w/ undetectable blood HIV are contagious
- _ lower blood HIV levels allowing for prolongation of life, most patients are below detectable limit
- Prenatal and postnatal drugs offer significant protection in neonate against AIDS
- Long term non-progesser population: have strong cellular immune response to HIV keeping disease in check, may be potential for augmentation in future therapy
- No vaccines
- Immune reconstitution inflammatory syndrome: successful restoration of immune system may lead to exaggerated immune attack on other microorganisms
- HIV resistance to individual to individual agents usually occurs
Drug combos
Multidrug combos prevent emergence of _ forms – and re-emergence of HIV
o RT is error prone – so mutagenesis
o Avoid – overlapping toxicities, metabolic activation – same analog of a base
resistant
_ class properties – HIV 1 and 2
1. All resemble nucleosides – require intracellular phosphorylation 2. Lack 3’ OH for continued polymerization of cDNA 3. Works on HIV 1 and 2 – some Hep. B. 4. Can cause hepatic damage, lactic acidosis at low frequency, can be fatal, alcohol can cause issues
Nucleoside inhibitors
_ class properties – HIV 1
1. Do not require intracellular phosphorylation (don’t resemble nucleosides) 2. Bind to reverse transcriptase adjacent to active site, causes conformational change (inhibiting it) 3. HIV 1 not 2 4. Crosses placenta and also in milk 5. Cause rash 6. Metabolized by P450 – many drug interactions (protease inhibitors) 7. Rapid resistance when alone – mutations in RT
Non-nucleoside inhibitor
_ Class properties– contributes aspartic acid to active site – resemble transition state of cleavage sequences Gag-Pol
1. In combo w/ reverse transcriptase inhibitor -> lower blood levels of HIV 2. Not a cure 3. HIV 1 but most work on both 4. orally administered 5. Resistance quickly when alone - Mutation in protease leads to drug resistance, - Transported by PGP drug transporter - Cross resistance possible
-Protease Inhibitor
: know that _ use the LTR in double stranded DNA to insert the HIV copy into the host genome
integrase
Interferon gamma is the one produced in the adaptive or cellular immune response
Activated by dsRNA
gamma is adaptive
Other interferon types (known as Type I) are produced by innate immune response One of these is used as a drug
_ class of drugs
Inhibitors of viral DNA polymerase and/or Hepatitis B Reverse Transcriptase
base analogs
Acyclovir (Zovirax, Sitavig)
Valacyclovir (Valtrex
this hydroxyl group which is analogous to a 5’ hydroxyl of a nucleoside.
They all require metabolic activation to work PHOSPHORYLATION
All these base analogs become phosphorylated at the hydroxyl which is the analog of the DNA base 5’ hydroxyl.
All but ribavirin you have to take the monophosphate to the di, to the triphosphate
Drug affecting RNA -
Ribavirin - base analog
All but ribavirin you have to take the monophosphate to the di, to the triphosphate
Inhibitor of HSV attachment -
Docosanol
Need to know docosanol as something that is used against a DNA virus but blocks the attachment step.
DNA virus attach, penetrate on coat, transcribe, replicate, assemble, release etc.
With herpes in particular, and some other DNA viruses they bring with them on the penetration step a metabolic enzyme, _ and they bring a DNA polymerase that is different from our DNA polymerases
thymidine kinase
Acyclovir is guanine base attached to weird carbohydrate chain. Acyclovir gets into cells all over the body but it is first phosphorylated by the _
viral kinase
A metabolic filiter. You really only start activating acyclovir in a herpes infected cell (beautiful property, directed where you want it to be placed) Thymine kinase is not the target of action, we merely exploit it to get the directed formation of the active drug. So in the infected cell you form mainly with the viral thymidine kinase an acyclovir monophosphate. So acyclovir monophosphate gets formed inside of the virus infected cell. Then cellular enzymes take over and make the di and triphosphate.’
Once you get to acyclovir triphosphate you now have the active drug which can do about three things to the virus infected cell
It can compete with _ that the viral DNA polymerase is trying to use to make new genomes to replicate.
Acyclovir triphosphate can be recognized by the polymerase and be incorporated into new DNA.
You get chain termination if the acyclovir was incorporated into the new strain
compete with dGTP
This stop the manufacture of new DNA. So two ways of stopping the DNA: competing for the use of dGTP at the active site and then stopping polymerization once it’s incorporated.
not only that but this unusual incorporated structure is now a new chemical that is also an inhibitor of viral DNA polymerase
Acyclovir
herpes or CMV mainly?
herpes
HSV 1/2 and VZV
it is a prodrug of acyclovir
It’s a valine ester so it improves oral absorption
Its basically acyclovir …they have the same scheme of biologic activity
Valacyclovir (Valtrex
herpes
HSV 1/2 and VZV
Need to know Ganciclovir and Valganciclovir because they were developed to be more effective against herpes or CMV.
Ganciclovir and Valganciclovir more effective against CMV.
Prophylaxis & Treatment of CMV
Mechanism just like acyclovir, in a herpes infection can be activated by viral thymidine kinase just not as good as acyclovir but CMV has a different enzyme that it brings in known as _. This kinase can phosphorylate ganciclovir as the first step in metabolic activation
Like acyclovir you get ganciclovir triphosphate and inhibits dGTP and DNA polymerase
UL97 kinase
HBV a DNA virus Reverse transcriptase (RT) is about 50% homologous with HIV RT
Like HIV, HBV RT can be selectively targeted with several _ Drugs
Base Analog
Lamivudine DNA and Retro cirsus
competes with dCTP for reverse transcriptase action
