antiviral (Dr. Cochrane) Flashcards

1
Q

What is CC50?

A

Drug concentration at which reduces cell viability by 50%

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2
Q

How to find selectivity (SI) or therapeutic index (TI)?

A

CC50/IC50

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3
Q

What does a high TI/SI indicate?

A

drug is more selective to the virus targeted

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4
Q

what is drug clearance affected by?

A

i) metabolism in liver
ii) excretion through kidney/gut

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5
Q

Factors to consider when developing antivirals

A

i) toxicity of drug (try to minimize)
ii) efficacy of drug (better if done in low conc)
iii) drug delivery (how is the drug delivered to site of infection)
iv) drug clearance
v) how quick does drug resistance occur in virus?

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6
Q

Ways to deliver drug to targeted site

A

i) gut
ii) IV, inhalation, topical
iii) directly to site of infection (reduce toxicity while maximize drug efficacy)

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7
Q

What happens after pattern recognition receptors are activated?

A

signaling induced through IRF3/7 or NFkB
–> express interferons + proinflammatory cytokines

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8
Q

Pattern recongition receptors found on cell surface

A

TLR2,4,6

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9
Q

Pattern recongition receptors found on endosome

A

TLR3,7,8,9

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10
Q

Pattern recongition receptors found in cytoplasm

A

RIG-1, cGAS

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11
Q

What does TLR2,4 detect?

A

viral coat proteins

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12
Q

What does TLR7,8 detect?

A

ssRNA

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13
Q

What does TLR3, MDA5, RIG-1 detect

A

dsRNA

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14
Q

What does cGAS detect?

A

DNA

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15
Q

What does TRL9 detect?

A

hypomethylated CpG DNA

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16
Q

what PRR detects dsRNA?

A

TLR3, MDA5, RIG-1

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17
Q

what PRR detects DNA?

A

cGAS

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18
Q

what PRR detect viral coat proteins?

A

TLR2,4

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19
Q

What PRR detect hypomethylated CpG DNA?

A

TLR9

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20
Q

What PRR detect ssRNA?

A

TLR7,8

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21
Q

What happens after interferon interacts with its receptor?

A

signalling –> increase interferon-stimulated genes (ISG) expression
–> increase the cells’ ability to repsond and block virus replication

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22
Q

Types of interferon present

A

i) type I
ii) type II
iii)type III

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23
Q

examples of type 1 interferon

A

interferon alpha, beta

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24
Q

examples of type II interferon

A

interferon gamma

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25
Q

examples of type III interferon

A

interferon pheta

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26
Q

where are type I interferons found?

A

all nucleated cells

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27
Q

Where are type II interferons made?

A

T helper cells, NK cells, CD8 killer cells after they are activated

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28
Q

Examples where immune system leads to serious clinical outcomes

A

immune system hyperactivated (too much cytokines)
–> systemic inflammatory response syndrome (SIRS) or ARDS in Covid
–> multi-organ failure, systemic damage

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29
Q

Where is interferon treatment applied to?

A

hepatitus B, C with interferon alpha
–> more than 24 weeks

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30
Q

possible side effects of interferon treatment

A

have significant side effect reducing quality of life

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31
Q

Alternative approach to using interferon

A

activate innate immune system with TLR7/8 agonist (Imiquimod)
–> treat warts (HPV)

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32
Q

drugs that inhibit viral entry

A

i)Miraviroc
ii)T20
iii)Sunitinib (inhibits AAK1, GAK)
iv) lenacapavir (HIV-1, by binding to capsid)

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33
Q

How does Miraviroc work?

A

binds to CCR5 coreceptor –> compete with HIV-1 Gp120

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34
Q

How does T20 work?

A

mimic one of helical bundles
–> prevent six helical bundle from forming

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35
Q

Drugs that inhibit endosome release

A

i) chloroquine
ii) amantidine

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36
Q

How does chloroquine work?

A

prevent acidification of endosome needed for many virus
–> absorb protons to prevent pH change

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37
Q

How does amantidine work?

A

bind to M2 ion channel on influenza A virus
–> block ion flow

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38
Q

Why amantidine no longer recommmended for treatment?

A

lots of resistant virus formed

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39
Q

Drugs that inhibit viral genome replication

A

acyclovir

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40
Q

How does acyclovir work?

A

recognize and phosphorylate thymidine kinase of herpes virus

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41
Q

What viruses do acyclovir work on?

A

herpes virus

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42
Q

Herpes inhibitors present

A

i) Acyclovir (phosphorylate thymidine kinase)
ii) other chain terminators (e.g. famciclovir and other drugs with -vir)
iii)Foscarnet

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43
Q

How does Foscarnet work?

A

block PPi binding site in polymerase
–> prevent PPi being cleaved from deoxynucleotide triphosphate

44
Q

Concentration of foscarnet needed to inhibit viral polymerase

A

100 fold lower than cellular DNA polymerase is inhibited

45
Q

How do drugs inhibit viral reverse transcription in HIV-1?

A

i) these drugs lack 3’OH in ribose
–> cannot add next base
ii) induce conformational change by binding to other sites on RT
–> affect polymerization site

46
Q

Why are inhibitors for viral reverse transcription able to incorporate in DNA?

A

lack 3’ to 5’ exonuclease in reverse transcriptase

47
Q

other infections where HIV-1 NRTi inhibitors are used on

A

HBV (lamuvidine, tenofovir)

48
Q

How does tenofovir work?

A

also facilitate chain termination even tho it has 3’OH

49
Q

How does non-nucleoside reverse transcriptase inhibitors (NNRTi) work?

A

bind to other site
–> induce conformational change in RT that changes polymerase active site

50
Q

Drugs that inhibits integration of HIV-1

A

i) dolutegravir
ii) cabotegravir

51
Q

why does dolutegravir have high barrier to drug resistance?

A

i) long plasma half-life
ii) slow dissociation rate

52
Q

what’s special abt cabotegravir?

A

long half life
–> can be formulated as nanoparticle injection

53
Q

drugs that inhibit HIV-1 capsid interaction

A

lenacapavir

54
Q

How does lenacapavir work?

A

bind to HIV capsid in a pocket between capsid protein in hexamers

55
Q

Effect of using lenacapvir in HIV-1 life cycle

A

i) Viral entry – by interacting with sites that help traffick viral core to nucleus
–> virus stay in cytoplasm
ii) Viral core assembly
–> interfere with capsid-capsid interaction of Gag
–> prevent viral particle assembly + release

56
Q

How does inhibitors to HIV-1 protease work

A

bind to catalytic site of HIV-1 protease
–> mimic transition state of substrate during rxn

57
Q

Describe HIV-1 treatment evolution

A

i) first used AZT, not effective after couple of months
ii) combine multiple drugs to lower the chance of virus obtaining resistance on all of the drugs

58
Q

Standard therapy for HCV?

A

interferon + ribavirin

59
Q

newer treatment for HCV

A

combination of drugs that target different virus coded proteins (NS3 protease, replicase)

60
Q

What does the newer treatment for HCV target

A

NS3 protease, NS5A&B replicase

61
Q

What is targeted within SARS-Cov2?

A

i) viral protease
ii) viral replicase

62
Q

how does viral protease affected by drug?

A

prevent processing of viral polyprotein precursors needed for viral replication

63
Q

Drugs that target viral protease of SARS-Cov2

A

Paxlovid
–> nirmatrelvir + rotonavir

64
Q

Strategies used to target viral replicase of SARS Cov-2

A

i) stalling by replacing ATP with RTP – elongation barrier after three nt added – RdRp stalling

ii)induce hypermutation (increase rate of forming defective viral genome)

65
Q

Drugs used to target viral replicase of SARS-Cov2

A

remdesivir –> stalling
molnupiravir, favipiravir
–> hypermutation

66
Q

How does molnupiravir and favipiravir work?

A

induce hypermutation (increase rate of forming defective viral genome)

67
Q

How does remdesivir work?

A

stalling by replacing ATP with RTP – elongation barrier after three nt added – RdRp stalling

68
Q

How is viral release inhibited by drugs?

A

i)target neuraminidase by mimicking its substrate
–> unable to cleave sialic acid
–> cannot leave the cell and infect others
ii) lenacapavir by binding to capsid that prevent virus assembly and release
iii) Nilotinib –> prevent assembly plus release of Ebola

69
Q

Function of viral neuraminidase

A

cleaves terminal sialic acid from surface glycoprotein
–> prevent re-infection + allow virus to leave and infect others

70
Q

When can inhibitors for neuraminidase be used?

A

i) 36 to 48 hrs after onset of illness
ii) can be used before or after exposure of influenza A and B (prevent disease)

71
Q

Alternate approaches to drug development

A

i) re-purpose FDA approved drugs
ii) develop compounds that prevent virus to use cellular processes

72
Q

Examples of drugs being re-purposed

A

i) Lamuvidine –> HIV-1, HBV
ii) Cyclosporine A
iii) Nilotinib

73
Q

What virus can ribavarin be used in?

A

HCV, RSV

74
Q

What are the proposed mechanisms for ribavirin?

A

i) Inhibit inosine monophosphate dehydrogenase (IMPDH)
–> reduce GTP available
ii) modulate immune function thru T helper type 1
iii) inhibit RNA 5’ capping –> recognized by immune system
iv) inhibit viral RNA polymerase
v) increase mutation frequency

75
Q

the effect of inhibiting RNA 5’ capping to virus

A

less stable RNA, get recognized by immune system

75
Q

Original function of cyclosporin A

A

as a calcineurin inhibitor that act on T cells
–> immunosuppressive drug to block t cell proliferation

76
Q

What does cyclosporin A act on

A

cycophilin A –> proline cis0trans isomerase

77
Q

Which viruses do cyclosporin A act on?

A

HCV, HIV

78
Q

How does cyclosporin A act on HCV?

A

dissociate cyclophilin A from replicase
–> stop replication

79
Q

How does cyclosporin A act on HIV?

A

destabilize capsid
–> stop nuclear import of viral genome, block viral infection

80
Q

Where is cyclophilin A found in HCV?

A

part of replicase complex

81
Q

Where is cyclophilin A found in HIV?

A

binds to incoming viral capsid
–> stabilize it to allow import into nucleus

82
Q

Drug that target viral glycoprotein maturation

A

castanospermine

83
Q

How does castanospermine work?

A

inhibits ER alpha-glucosidase I
–> stop removal of terminal glucose on N-linked glycans
–> disrupt folding of viral proteins

84
Q

What does castanospermine act on

A

ER alpha-glucosidase I

85
Q

Which virus does castanospermine act on?

A

Dengue virus (all 4 serotypes)
–> no effect on yellow fever, west nile virus

86
Q

Original purpose of nilotinib

A

cancer drug through inhibiting ABL of BCR-ABL involved in modulating cell signalling

87
Q

What is nilotinib re-purposed to?

A

Ebola virus –> reduce production of viral particles

88
Q

How does nilotinib help to stop virual growth?

A

ABL phosphorylation needed on VP40 of Ebola
–> bind to ABL portion will stop viral particles from leaving

89
Q

What are the targets for drugs that inhibit membrane trafficking

A

AAK1, GAK

90
Q

How does inhibitors of AAK1 and GAK have an effect on virus?

A

affect virus entry and release
–> affect intracellular trafficking of viral particle

91
Q

What does AAK1 and GAK help virus?

A

acts as kinase regulators for AP1 and 2
–> essential for HCV infection

92
Q

Which viruses do inhibitors on AAk1 and GAK work?

A

HCV, West nile, Zika, dengue, ebola

93
Q

What happens if inhibitors for membrane trafficking are added post-infeciton?

A

no effect on viral RNA replication

94
Q

A host mechanism where durgs can use to manipualte

A

RNA splicing

95
Q

Viruses that uses alternative RNA splicing

A

HIV-1, adenovirus, influenza, papilloma, herpes

96
Q

Drugs tested to alter RNA processing

A

digoxin

97
Q

Original purpose of digoxin

A

inhibit Na+/K+ ATPase
–> more Ca2+ accumulate
==> stronger contractions

98
Q

Why is digoixn not a viable treatment

A

limited therapeutic index
–> need high dosages for it to work

99
Q

Which virusesis digoxin effective on?

A

HIV, adenovirus, SARS-Cov2

100
Q

Strategies to prepare for future pandemic

A

i) vaccine
ii) virus-directed antiviral
iii) host-directed antivirals

101
Q

Advantage of using host-directed antivirals

A

i) resistance not as worried as interaction with host is crucial
ii) broad-spectrum

102
Q

Problems of using vaccine

A

short shelf-life may limit ability to store vaccines

103
Q

How to develop host-directed antivirals

A

i) generate population of cells with CRISPR with one gene disrupted in each cell
ii) infect cells with virus –> virus kill susceptible cells
iii) harvest surviving cells, isolate DNA
–> identify the killssgRNA sequence
iv) identify antiviral properties of known inhibitors of identified proteins

104
Q

Issue of using virus-directed antiviral

A

specificty of antivirals might limit effectiveness of treatment
–> use combination of drugs to slow down buildup of resistance