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MDCM626 > Antiviral > Flashcards

Antiviral Flashcards

1
Q

Infection of cells by virus

Attachment

Methods of penetration (3)

Incorporation of DNA/RNA

Self assembly

Release

A
  • Viral cell surface glycoproteins bind to host
  1. Injection of viral core through the cell membtrane using enzymes (less relevant for treatment)
  2. Entry of virion by one envelope with the plamsa membrane (fusion)
  3. Endocytosis
  • Early genes, Late Genes
  • Produce multiple copies of the virus for export
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2
Q

How do viruses hijack?

A
  • 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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3
Q

Respiratory Syncytial Virus Disease

Leading cause?

Looks like a?

Treatment?

A
  • Lower respiratory tract infections
  • COLD
  • Ribavirin and Palivizumab
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4
Q

Common structure of Nucleoside based antivirals?

A
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5
Q

Ribavirin

Activated?

Spectrum?

MOA?

Low?

Forms?

AEs?

A
  • 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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6
Q

MOA of Nucleoside Analogues

Activations + kinases?

Selectivity?

Resistance?

A
  • Phosphorylation at 5-OH
  • Viral kinases, viral polymerases differ with human
  • Mutation of kinase
  • Mutation at polymerase
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7
Q

Mechanism of nucleosides

A
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8
Q

Palivizumab, is used for?

A
  • Prevention of RSV
  • Injectable MAB (monoclonal antibody)
  • Premature births, chronic lung disease, congenital heart disease
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9
Q

Influenza is caused by?

A

An RNA virus

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

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10
Q

Influenza

RNA polymerase

Neuraminidase

Hemaglutinin

M2

A
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11
Q

Antigenic Drift and Shift

Genes that are mostly involved?

A
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12
Q

Amantadine and Rimantadine

MOA

ADME

T1/2

Metabolism and excretion

A
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13
Q

Neuraminidase inhibitors do what?

A
  • Mimic the transition state of Sialic acid
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14
Q

NA inhibitors

Names

Which ones work best for what? Which one is available in oral?

Potency in relation to pocket?

A
  • 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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15
Q

Herpes Virus

Cycle

A

A DNA virus

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16
Q

Human Herpes virus classifications

A
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17
Q

Cycle drug therapeutic strategy

A

No cure fo the latent stage

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18
Q

Herpes substructure MOA 3

A

Changes allow drug to be seen by viral not host

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19
Q

Acylovir and Valacyclovir

MOA? Interferes with?

Selectivity?

Targets?

Low?

A

Interference with viral nucleic acid replication

MOA

Activation, Selectivity, Targets

Viral kinase- selectivity

Oxidation inactivates drug

Low F

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20
Q

Acylcovir

How does it terminate?

A
  • Is added to chain elongation
  • Then at the 3’ position does not contain OH stops elongation
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21
Q

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

A
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22
Q

Acylcovir and Valacyclovir

Summary

A
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23
Q

Famiciclovir and Penciclovir

Spectrum

MOA

DMPK differences

availability

A

Viral polymerase inhibitor

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24
Q

CMV

DRugs

A
  • Ganciclovir and Valganciclovir
  • Similar things to Acyclovir and valacylovir
    *
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25
Q

Ganciclovir and Valganciclovir

MOA

Selectivity

Toxicity

Resistance

spectrum

forms

A
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26
Q

PRonucleotide strategy

Mutations an how to overcome

A
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27
Q

Over coming resistance

what is added?

what are the drugs?

A
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28
Q

Cidofovir

MOA

Toxicity

DMPK

Spectrum

A

More toxic of a drug

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29
Q

Foscarnet

MOA

DMPK

Activation?

(IOnic)

Spectrum toxicity?

A

Toxic

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30
Q

Coverage chart

A

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

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31
Q

HIV

A
32
Q

HIV targets

4

A
  1. Block HIV docking with 120 and 41 gp
  2. Reverse transcriptase
  3. HIV protease
  4. HIV integrase
33
Q

Inhibiton of HIV reverse transcriptase

A

NRTIs and NNRTIs

34
Q

Zidovudine

A

NRTI

No OH at 3’ so you virus cannot replicate

activation via phosphorylation

35
Q

SOme NRTIs

A
36
Q

Toxicities related to NRTIs

Class toxicity?

3

Prevent body frrom producing?

Increase and cause?

Accumulations?

What drugs dont have these?

A
  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

37
Q

NRTIS

Class toxicty

Decreased toxicity

A
  • Fatal lactic acidosis, and hepatic steatosis
  • Inverted steriochemistry decreases toxicity (kinase selectivity)
38
Q

NNRTIs

All available in what form?

Induce, inhibit or substrates of?

Highly optimized DMPK properties?

A

All orally bioavailable

39
Q

NNRTIs are act by doing what?

MOA and Toxicities

Not active against?

Which ones have SEs?

A

Allosteric modulators

40
Q

NNRTIs are highly?

A
41
Q

Inhibitors of HIV integrase

MOA?

Interactions with what other drugs?

What can change absorption?

Admin?

Active against?

DMPK

A

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
42
Q

HIV protease as a target for Therapy?

A
  • 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
43
Q

Mechanism of HIV protease

what is the key step that is mimiced

A

Protease Inhibitors mimic the transition state

44
Q

Inhibition of HIV protease by ligand with non-cleavable bonds

Side Chains?

Amide vs 2ndary OH

Transition state?

A
  • Alter potency, selectivity, and PK properties
  • Binding interactions ar active site, non-cleavable
  • Absolute configuration is vital for action
45
Q

HIV protease inhibitors

4

These molecules are? and Contain?

So there is lots of?

A
  • These are very greasy molecules and peptides, so lots of protease metabolize them and CYP450s metabolize lipids
46
Q

Order of resistances with NRTIS, INRTIS, PIs, NNRTIs?

A
  • NNRTIs–PIs—NRTIs–INSTIs least prone
47
Q

HIV protease inhibitors with improved properties?

Why?

Improved?

Still issues?

Resistance?

4

A
48
Q

Ritonavir a __ for PIs

Resistance

MOA?

What part of it is doing this?

A

Thiazole interferes with CYP3a4 by binding to Fe heme in the molecule deactivating it

49
Q

Why would you want to inhibit CYP3A4?

A
  • To reduce to concentration of other drugs needed to be effective
50
Q

Cobistat: 2nd Gen for?

MOA1 and 2

Acts on two main thing

the end result is?

same what?

A

Same interaction with Thiazole and inhition of MOA

Clinical uses and more

51
Q

Enfuvirtide and Maraviroc

MOA for both ADME

A
52
Q

Combination drug therapy for HIV in 2015

A
  • “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
53
Q

Future for HIV/AIDS Chemotherapy

A
54
Q

Viral hepatitis

Many types

prevention

A
55
Q

Anti HEP B agents

3

A
56
Q

Physiochemical and Clinical Properties of Interferons

Clinical application what are they?

Peptide?

Peg Alpha?

A
57
Q

Mechanisms and SEs of Interferons?

A
58
Q

Inferons are ___ on patients

A

Harsh on patient

Basically the worst flu youve ever had every day

59
Q

Life Cycle of Hep C

____ protease not?

NS3-4A Inhibitors

What do they end in?

WHat do they do?

A
60
Q

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?

A
61
Q

Interaction of Boceprevir with what site of the virus?

A
62
Q

Notes on Simeprevir

MOA
Uses
Spectrum
DMPK
SE

Interactions?

A
63
Q

Life cycle of HCV

A

NS5B RNA POLYMERASE

DRUGS

Sofosbuvir

Dasabuvir

64
Q

Sofosbuvir

1st in class?

MOA

Selectivity and Toxicity

DMPK

A
65
Q

Orthogonal Strategy for Activations of SofosBUVIR

A
66
Q

SofosBUVIR

Clinical spectrum

Minimal potential for?

AEs?

A
67
Q

Few options for NS5B

3

A

SofosBUVIR

DasaBUVIR

Ribivirin

68
Q

NS5A

4 Drugs?

affects all genotypes of HCV

A
  1. OmbitASVIR
  2. LedipASVIR
  3. ElbASVIR
  4. VelpatASVIR
69
Q

LedipASVIR

Structural feature?

MOA

Clinical uses

AEs?

Interactions?

Absorbance?

A
  • All have linear linker and B-turn mimic
70
Q

Combo therapies to Treat HCV

Safety and Toxicity?

Multicomponent cocktails?
HCV spectrum?

ADME/DMPK

Considerations?

A
71
Q

Combo harvoni- Ledipasvir/Sofosbuvir

Epclusa- Velpatasvir/Sofosbuvir

Dependent on?

A

PO dependent on H acidity

72
Q

Harvoni

MOA of both?

Free of?

SPectrum?

Interactions?

Overall?

A
73
Q

Viekra Pak for HCV

A
74
Q

Notes on Viekra Pak for HCV

A
75
Q

Notes on Zepatier

A
76
Q

Note on epclusa

A

MDCM626 (26 decks)

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