Antiviral Flashcards
Infection of cells by virus
Attachment
Methods of penetration (3)
Incorporation of DNA/RNA
Self assembly
Release
- Viral cell surface glycoproteins bind to host
- Injection of viral core through the cell membtrane using enzymes (less relevant for treatment)
- Entry of virion by one envelope with the plamsa membrane (fusion)
- Endocytosis
- Early genes, Late Genes
- Produce multiple copies of the virus for export
How do viruses hijack?
- Hijacking host cells, viruses have to convert vDNA/vRNA into host DNA/RNA
- For synthesis of new viral particls, must convert host DNA/RNA into vRNA/vDNA
- Interference with DNA/RNA replication cycles blocks the spread of viruses
- Many drugs interfere with these processes (viral polymerases/reverse transcriptase)
Respiratory Syncytial Virus Disease
Leading cause?
Looks like a?
Treatment?
- Lower respiratory tract infections
- COLD
- Ribavirin and Palivizumab
Common structure of Nucleoside based antivirals?
Ribavirin
Activated?
Spectrum?
MOA?
Low?
Forms?
AEs?
- Activated via viral kinase
- Broad- DNA and RNA viruses (RSV, Influenza A+B, HIV, HHV, HCV)
- Intracellular tiphosphorylation and inhibition of virus specific DNA and RNA polymerases
- Resistance is low to susceptible viruses
- PO, IV, aerosol
- Minor GI complaints
MOA of Nucleoside Analogues
Activations + kinases?
Selectivity?
Resistance?
- Phosphorylation at 5-OH
- Viral kinases, viral polymerases differ with human
- Mutation of kinase
- Mutation at polymerase
Mechanism of nucleosides
Palivizumab, is used for?
- Prevention of RSV
- Injectable MAB (monoclonal antibody)
- Premature births, chronic lung disease, congenital heart disease
Influenza is caused by?
An RNA virus
Three species spread (Fowl–>Pig–> human)
Influenza
RNA polymerase
Neuraminidase
Hemaglutinin
M2
Antigenic Drift and Shift
Genes that are mostly involved?
Amantadine and Rimantadine
MOA
ADME
T1/2
Metabolism and excretion
Neuraminidase inhibitors do what?
- Mimic the transition state of Sialic acid
NA inhibitors
Names
Which ones work best for what? Which one is available in oral?
Potency in relation to pocket?
- Oseltamivir
- Zanamivir
- Peramivir
- Oseltamivir is a prodrug ethyl gets cleaved to reveal carboxylic acid only oral drug
- Guanidine group on Zana and Pera decrease oral availability
- Osel and Pera both have hydrophobic portions on the 6 C so they interact better with hydrophobic pocket.
Herpes Virus
Cycle
A DNA virus
Human Herpes virus classifications
Cycle drug therapeutic strategy
No cure fo the latent stage
Herpes substructure MOA 3
Changes allow drug to be seen by viral not host
Acylovir and Valacyclovir
MOA? Interferes with?
Selectivity?
Targets?
Low?
Interference with viral nucleic acid replication
MOA
Activation, Selectivity, Targets
Viral kinase- selectivity
Oxidation inactivates drug
Low F
Acylcovir
How does it terminate?
- Is added to chain elongation
- Then at the 3’ position does not contain OH stops elongation
Acylcovir has low toxicity what are the 3 factors that contribute to this?
Acylcovir and Valacyclovir
Summary
Famiciclovir and Penciclovir
Spectrum
MOA
DMPK differences
availability
Viral polymerase inhibitor
CMV
DRugs
- Ganciclovir and Valganciclovir
- Similar things to Acyclovir and valacylovir
*
Ganciclovir and Valganciclovir
MOA
Selectivity
Toxicity
Resistance
spectrum
forms
PRonucleotide strategy
Mutations an how to overcome
Over coming resistance
what is added?
what are the drugs?
Cidofovir
MOA
Toxicity
DMPK
Spectrum
More toxic of a drug
Foscarnet
MOA
DMPK
Activation?
(IOnic)
Spectrum toxicity?
Toxic
Coverage chart
Orange highlight more toxic
When there is resistance good to use
Cido anf Foscarnet - only injection
Pen and Fam - Tab and Topical
Acyclo and Valacy- Ointment injection
look at forms available
HIV
HIV targets
4
- Block HIV docking with 120 and 41 gp
- Reverse transcriptase
- HIV protease
- HIV integrase
Inhibiton of HIV reverse transcriptase
NRTIs and NNRTIs
Zidovudine
NRTI
No OH at 3’ so you virus cannot replicate
activation via phosphorylation
SOme NRTIs
Toxicities related to NRTIs
Class toxicity?
3
Prevent body frrom producing?
Increase and cause?
Accumulations?
What drugs dont have these?
- NRTIs inhibiting DNA γ-polymerase à disrupt β-oxidation, the Kreb’s cycle, and transcription of essential enzymes needed for ATP production
- Increased triglycerides cause hepatic steatosis.
- Lactic acid accumulates more rapidly than it can be excreted by the kidney. (Lactic acidosis)
Lamivudine and Emtricabine are Enantiomers you can tell by the structure and this gives them less toxicity because the viruse recognizes them but the host doesnt
NRTIS
Class toxicty
Decreased toxicity
- Fatal lactic acidosis, and hepatic steatosis
- Inverted steriochemistry decreases toxicity (kinase selectivity)
NNRTIs
All available in what form?
Induce, inhibit or substrates of?
Highly optimized DMPK properties?
All orally bioavailable
NNRTIs are act by doing what?
MOA and Toxicities
Not active against?
Which ones have SEs?
Allosteric modulators
NNRTIs are highly?
Inhibitors of HIV integrase
MOA?
Interactions with what other drugs?
What can change absorption?
Admin?
Active against?
DMPK
INSTIs
- Chelate catalytic metal in integration which inhibits the insertion of viral DNA into the host DNA
- Actie against HIV strains resistant to other antiretroviral drugs (combo therapy)
- PO, interasctions with some NRTIs (glucuronidation), and rifampin (CYP3A4)
- Optimized PK and SE profiles
- Metal interaction and absorption
- Optimized PK and SE profiles
HIV protease as a target for Therapy?
- The protease cleaves specific peptide bonds by addition of water (hydrolysis)
- HIV protease is an enzyme crucial for post-translational modification of immature core proteins into structural proteins
- PI- Core proteins of HIV-1 are produced as part of long polypeptides that are cut into smaller pieces by proteaseto create functional and mature proteins. With the inhibition of protease, new viral particles cannot mature and do not become infectous
Mechanism of HIV protease
what is the key step that is mimiced
Protease Inhibitors mimic the transition state
Inhibition of HIV protease by ligand with non-cleavable bonds
Side Chains?
Amide vs 2ndary OH
Transition state?
- Alter potency, selectivity, and PK properties
- Binding interactions ar active site, non-cleavable
- Absolute configuration is vital for action
HIV protease inhibitors
4
These molecules are? and Contain?
So there is lots of?
- These are very greasy molecules and peptides, so lots of protease metabolize them and CYP450s metabolize lipids
Order of resistances with NRTIS, INRTIS, PIs, NNRTIs?
- NNRTIs–PIs—NRTIs–INSTIs least prone
HIV protease inhibitors with improved properties?
Why?
Improved?
Still issues?
Resistance?
4
Ritonavir a __ for PIs
Resistance
MOA?
What part of it is doing this?
Thiazole interferes with CYP3a4 by binding to Fe heme in the molecule deactivating it
Why would you want to inhibit CYP3A4?
- To reduce to concentration of other drugs needed to be effective
Cobistat: 2nd Gen for?
MOA1 and 2
Acts on two main thing
the end result is?
same what?
Same interaction with Thiazole and inhition of MOA
Clinical uses and more
Enfuvirtide and Maraviroc
MOA for both ADME
Combination drug therapy for HIV in 2015
- “An ARV regimen generally consists of two NRTIs (one of which is FTC or 3TC) plus an INSTI, NNRTI, or PKenhanced PI. Selection of a regimen should be individualized on the basis of virologic efficacy, potential adverse effects, pill burden, dosing frequency,
- Combinations consider cross resistance within classes it is common but not between classes
- So chemotherapy combines classes
Future for HIV/AIDS Chemotherapy
Viral hepatitis
Many types
prevention
Anti HEP B agents
3
Physiochemical and Clinical Properties of Interferons
Clinical application what are they?
Peptide?
Peg Alpha?
Mechanisms and SEs of Interferons?
Inferons are ___ on patients
Harsh on patient
Basically the worst flu youve ever had every day
Life Cycle of Hep C
____ protease not?
NS3-4A Inhibitors
What do they end in?
WHat do they do?
Anti Hep C agents
NS3/4A Is
2 of them
Combo with?
Peptides size wise what does this mean?
metabolism?
Interactions with drugs
which one has severe skin rxn?
Interaction of Boceprevir with what site of the virus?
Notes on Simeprevir
MOA
Uses
Spectrum
DMPK
SE
Interactions?
Life cycle of HCV
NS5B RNA POLYMERASE
DRUGS
Sofosbuvir
Dasabuvir
Sofosbuvir
1st in class?
MOA
Selectivity and Toxicity
DMPK
Orthogonal Strategy for Activations of SofosBUVIR
SofosBUVIR
Clinical spectrum
Minimal potential for?
AEs?
Few options for NS5B
3
SofosBUVIR
DasaBUVIR
Ribivirin
NS5A
4 Drugs?
affects all genotypes of HCV
- OmbitASVIR
- LedipASVIR
- ElbASVIR
- VelpatASVIR
LedipASVIR
Structural feature?
MOA
Clinical uses
AEs?
Interactions?
Absorbance?
- All have linear linker and B-turn mimic
Combo therapies to Treat HCV
Safety and Toxicity?
Multicomponent cocktails?
HCV spectrum?
ADME/DMPK
Considerations?
Combo harvoni- Ledipasvir/Sofosbuvir
Epclusa- Velpatasvir/Sofosbuvir
Dependent on?
PO dependent on H acidity
Harvoni
MOA of both?
Free of?
SPectrum?
Interactions?
Overall?
Viekra Pak for HCV
Notes on Viekra Pak for HCV
Notes on Zepatier
Note on epclusa
