Antiviral Flashcards by Jon Beckloff

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

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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)

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Respiratory Syncytial Virus Disease

Leading cause?

Looks like a?

Treatment?

Lower respiratory tract infections
COLD
Ribavirin and Palivizumab

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Common structure of Nucleoside based antivirals?

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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

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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

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Mechanism of nucleosides

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Palivizumab, is used for?

Prevention of RSV
Injectable MAB (monoclonal antibody)
Premature births, chronic lung disease, congenital heart disease

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Influenza is caused by?

An RNA virus

Three species spread (Fowl–>Pig–> human)

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Influenza

RNA polymerase

Neuraminidase

Hemaglutinin

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Antigenic Drift and Shift

Genes that are mostly involved?

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Amantadine and Rimantadine

MOA

ADME

T1/2

Metabolism and excretion

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Neuraminidase inhibitors do what?

Mimic the transition state of Sialic acid

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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.

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Herpes Virus

Cycle

A DNA virus

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Human Herpes virus classifications

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Cycle drug therapeutic strategy

No cure fo the latent stage

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Herpes substructure MOA 3

Changes allow drug to be seen by viral not host

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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

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Acylcovir

How does it terminate?

Is added to chain elongation
Then at the 3’ position does not contain OH stops elongation

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Acylcovir has low toxicity what are the 3 factors that contribute to this?

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Acylcovir and Valacyclovir

Summary

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Famiciclovir and Penciclovir

Spectrum

MOA

DMPK differences

availability

Viral polymerase inhibitor

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CMV

DRugs

Ganciclovir and Valganciclovir
Similar things to Acyclovir and valacylovir
*

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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

1. Block HIV docking with 120 and 41 gp 2. Reverse transcriptase 3. HIV protease 4. 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?

1. NRTIs inhibiting DNA γ-polymerase à disrupt β-oxidation, the Kreb's cycle, and transcription of essential enzymes needed for ATP production 2. Increased triglycerides cause hepatic steatosis. 3. 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

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?