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Medicinal Chemistry - Winter > 18, 19 - Antiviral > Flashcards

18, 19 - Antiviral Flashcards

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1
Q

Do viruses contain DNA and RNA?

A

Contain DNA or RNA surrounded by uncomplicated protein coat (serves as cell membrane)

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2
Q

Do viruses have a lipid bilayer?

A

More complex viruses do

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3
Q

Can viruses replicate on their own?

A
  • No, they require living cells to do so

- Exist at interface of living and non-living organisms

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4
Q

Do viruses conduct their own metabolic processes?

A

No, dependent on host cell

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5
Q

What happens to viruses during replication in host cells?

A

Lose organized structure

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6
Q

What are the shapes of viruses?

A
  • Helical
  • Polyhedral
  • Spherical
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7
Q

What happens when DNA virus enters a host cell?

A
  • Enters nucleus of host cell, where viral DNA is transcribed into mRNA by host cell RNA polymerase
  • mRNA is translated into virus-specific proteins that facilitate assembly, maturation, and release of newly formed virus into surroundings
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8
Q

What is the difference between DNA and RNA viruses?

A
  • DNA viruses rely on host cell to synthesize mRNA

- RNA viruses rely on enzymes in the virus itself to synthesize mRNA

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9
Q

What features are used to characterize viruses?

A
  • Nucleic acid content (DNA or RNA)
  • Viral morphology (helical, icosahedral)
  • Site of replication in cell (cytoplasm or nucleus)
  • Coating (enveloped or non-enveloped)
  • Serological typing (antigenic signatures)
  • Cell types infected (B or T lymphocytes, monocytes)
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10
Q

Estimated that viruses cause __% of infectious diseases in developing countries

A

60%

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11
Q

Why is development of antivirals difficult?

A
  • Viruses won’t grow in simple culture media
  • Need mammalian-derived cell cultures, making drug screening techniques very difficult
  • Viruses have much simpler biochemistry than bacteria, meaning fewer potential drug targets
  • Viral infections don’t appear until well established, making tx more difficult
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12
Q

What is an antiviral?

A

Chemical compound that may inhibit various biochemical targets or arrest biochemical events

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13
Q

What are the 7 stages of viral infection?

A
  • Absorption (attachment to specific receptors)
  • Penetration (entry of virus into cell)
  • Uncoating (release of viral nucleic acid from coat)
  • Transcription (production of viral mRNA)
  • Translation (synthesis of viral proteins and nucleic acids, using host cell processes)
  • Assembly (of viral particles)
  • Release (of virus from cell by budding and rupture)
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14
Q

What is chemoprophylaxis?

A

Administration of medication for prevention of disease or infection

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15
Q

Which drugs are adamantanamines? What is their mechanism?

A
  • Amantadine and rimantadine
  • Interfere w/ penetration of host cells by viruses and block early stage replication (uncoating); also affect a later step involved in viral assembly
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16
Q

What are adamantanamines used for?

A

Prevention and treatment of influenza type A

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17
Q

What are neuraminidase inhibitors?

A
  • Enzymes that function in early activation steps of the virus
  • Important in enhancing penetration of viruses into host cells
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18
Q

Which drugs are neuraminidase inhibitors? What does each drug do?

A
  • Zanamivir – inhibits neuraminidase by binding to active site of sialic acid-sugar bond cleavage (guanidino group key for competitive inhibition)
  • Oseltamivir – orally active competitive inhibitor (prodrug, ethyl ester allows for oral bioavailability; non-polar 3-pentyl group key for max binding)
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19
Q

What is the function of neuraminidase?

A
  • Found on surface of virus
  • Cleaves sialic acid containing receptor
  • Neuraminidase specifically catalyzes breakdown of glycosides containing neuraminic acid
  • Allows for new virions to be released
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20
Q

What are interferons?

A
  • Extremely potent cytokines that possess antiviral, immunomodulating, and anti-proliferative actions
  • Synthesized by host cells in response to various inducers, and elicit anti-viral activity
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21
Q

What happens when interferons bind to cellular receptors?

A

Induce synthesis of a cascade of antiviral proteins

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22
Q

What do interferons inhibit to have anti-viral effects?

A
  • Viral penetration or uncoating
  • mRNA synthesis
  • Translation of viral proteins
  • Viral assembly and release
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23
Q

Interferons predominantly inhibit ____ synthesis

A

Protein

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24
Q

Which interferons are used clinically? For what purposes?

A
  • Interferon alpha used in recombinant form

- Interferon beta used for tx of MS

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25
Q

Which drugs are nucleoside antimetabolites?

A

Acyclovir and valacyclovir

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26
Q

What dosage forms is acyclovir available as? What is it used for?

A
  • Oral, injection, and ointment
  • Used for acute tx of herpes simplex (cold sores) and herpex zoster (chicken pox/shingles); and tx of initial episodes of herpes genitalis
  • Reduces viral shedding in shingles; also used for herpes simplex encephalitis
  • Doesn’t cure but decreases severity and length of outbreak
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27
Q

What is the difference between valacyclovir and acyclovir?

A

Valacyclovir is a pro-drug of acyclovir

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28
Q

What is the MOA of acyclovir?

A
  • Conversion to active monophosphate by viral thymidine kinase occurs faster by herpes virus infected cells than normal cells
  • Competitive inhibitor of viral DNA polymerase, and is incorporated into viral DNA during DNA synthesis; due to lack of “sugar” it terminates DNA elongation
  • Preferential uptake in herpes-infected cells
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29
Q

What is adefovir dipivoxil used for? What is its MOA?

A
  • Tx of chronic hepatitis B
  • Competitive inhibitor for hepatitis B virus reverse transcriptase, acting as a chain terminator
  • Adefovir dipivoxil = prodrug that is converted into adefovir
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30
Q

Which drugs are nucleoside antimetabolites? What is their general function?

A
  • Ganciclovir and penciclovir
  • Cidofovir
  • Cytarabine and idoxuridine
  • Ribavirin
  • Trifluorothymidine
  • Vidarabine
  • Sofosbuvir
  • Inhibit viral replication
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31
Q

Nucleoside antimetabolites are analogs of _____ and the modification ______

A
  • Analogs of acyclovir
  • Modification maintains activity against HSV, but increases activity against cytomegalovirus (CMV) infections (ganciclovir)
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32
Q

Where are ganciclovir and penciclovir phosphorylated? What happens after this?

A
  • Ganciclovir = phosphorlyated inside host cell; ganciclovir triphosphate incorporated into DNA and stops elongation
  • Penciclovir = phosphorlyated by viral thymidine kinase and competitively inhibits DNA elongation
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33
Q

What is cidofovir? What is its active form? What does it do?

A
  • Acyclic pyrimidine nucleotide analog of cytosine
  • Metabolized in vivo to active diphosphate
  • Inhibits viral replication via DNA synthesis interference
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34
Q

What are cytarabine and idoxuridine? What are their active forms? What do they do?

A
  • Synthetic pyrimidine analogs of cytidine and uridine respectively
  • Metabolically converted into active triphosphates
  • Incorporated into DNA during replication
  • Cytarabine blocks utilization of deoxycytidine
  • Idoxuribine replaces thymidine => faulty viral proteins
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35
Q

What is ribavirin? What is its active form? What does it do?

A
  • Guanosine analog w/ broad spectrum antiviral activity (both DNA and RNA)
  • Phosphorylated by adenosine kinase
  • Inhibits viral RNA polymerase
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36
Q

What is trifluorothymidine? What is its active form? What does it do?

A
  • Fluorinated analog of thymidine
  • Triphosphate is incorporated into viral DNA in place of thymidine
  • Causes faulty viral mRNA proteins (HSV-1)
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37
Q

What is vidarabine? What is its active form? What does it do?

A
  • Adenosine nucleoside analog
  • Triphosphate is active form
  • Triphosphate interferes w/ viral nucleic acid replication due to arabinose sugar
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38
Q

What is sofosbuvir? What is it used for?

A
  • Uridine nucleotide analog

- Used in combination w/ other drugs for tx of hepatitis C virus infection

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39
Q

What are the common complications of hepatitis C that lead to death?

A

Cirrhosis and liver cancer

40
Q

Which drug is sofosbuvir combined w/ for tx of hepatitis C? Does it treat the virus? How long is the tx?

A
  • Combined w/ ledipasvir
  • Provides essentially 100% cure rate
  • 12 weeks of tx
41
Q

Sofosbuvir is a substrate of _____

A

P-glycoprotein

42
Q

What is the MOA of the sofosbuvir/ledipasvir combination?

A

Inhibits NS5A (viral phosphoprotein)

43
Q

What is the active form of sofosbuvir? What does this do?

A
  • Triphosphate is active

- Serves as a defective substrate for viral RNA polymerase (inhibits RNA polymerase)

44
Q

What is important about sofosbuvir when comparing it to the nucleoside parent compound?

A
  • Sofosbuvir is masked to neutralize the charge so that it can be taken up into the cell
  • Cellular enzymes convert sofosbuvir to the monophosphate much faster than it converts parent nucleoside to monophosphate (so parent isn’t potent)
45
Q

What is the function of reverse transcriptase enzyme?

A

Used to generate complementary DNA from an RNA template

46
Q

What are the activities of retroviral reverse transcriptase?

A
  • RNA-dependent DNA polymerase
  • Ribonuclease H (enzyme that catalyzes cleavage of RNA)
  • DNA-dependent DNA polymerase
47
Q

Which drugs are used to control HIV infections?

A

Reverse transcriptase inhibitors

48
Q

What is required for the function of reverse transcriptase inhibitors?

A

Availability of purine and pyrimidine nucleosides and nucleotides

49
Q

What is special about azidothymidine?

A

Nucleoside reverse transcriptase inhibitor whose azido group increases lipophilic nature, making it easier to cross cell membrane

50
Q

What is an additional method to inhibit viral DNA synthesis?

A

Replace 3’-OH moiety of ribose sugar, which terminates elongation

51
Q

What is truvada? What is it used for?

A
  • Combination of tenofivir disoproxil and emtricitabine

- Used to prevent HIV infection in high risk individuals (reduces risk of infection by 50-100%)

52
Q

What happens to tenofovir disoproxil?

A

Prodrug that is hydrolyzed by esterases to yield monophosphate, which is phosphorylated to active triphosphate

53
Q

What is the MOA of tenofovir?

A
  • Tenofovir needs to be phosphorylated in 1 or 2 steps to diphosphate form
  • It then interferes, as a chain terminator, w/ reverse transcriptase reaction
54
Q

What is the model used to describe HIV reverse transcriptase?

A

Hand model

- Has a palm, 3 fingers, thumb, and extra finger (RNAseH)

55
Q

How can a viral cell develop resistance against nucleoside reverse transcriptase inhibitors?

A
  • Mutation that leads to discrimination or excision of an incorporated NRTI
  • Discrimination mutation = amino acid change that reduces selectivity of an NRTI over the correct nucleotide during DNA polymerization
56
Q

What is involved in the triple therapy for HIV?

A
  • Nucleoside reverse transcriptase inhibitor
  • Non-nucleoside reverse transcriptase inhibitor
  • Integrase inhibitor or protease inhibitor
57
Q

What is the benefit to non-nucleoside RTIs vs. nucleoside RTIs?

A
  • NNRTIs don’t require bioactivation by kinases to give phosphate
  • Bind to allosteric site of reverse transcriptase
  • Exhibit classical non-competitive inhibition pattern
58
Q

Why do non-nucleoside RTIs bind to allosteric sites of HIV-1 reverse transcriptase?

A
  • HIV-1 reverse transcriptase undergoes a series of conformational changes during viral replication
  • Intrinsic flexibility provides novel allosteric sites for inhibition
59
Q

What does allosteric binding cause?

A

Distorts enzyme so it can’t form the enzyme-substrate complex at a normal rate

60
Q

What is the newest method to identify potential allosteric inhibitors?

A
  • X-ray crystallographic fragment screening

- Take crystals of reverse transcriptase and incubate w/ drug fragments using x-ray crystallography, identify binders

61
Q

Describe the fragment screening for non-nucleoside RTI anti-HIV drugs?

A

1) Binding site comprised of 3 binding pockets
2) Crystallographic screening locates molecule fragments that bind 1, 2, or all 3 pockets
3) Lead compound is designed by organizing all 3 fragments around a core template
4) Growing out of a single fragment

62
Q

How does the nucleic acid pass through the HIV reverse transcriptase hand model?

A
  • Nucleic acid template passes between the thumb and finger domains where active site of DNA polymerisation is located
  • Extra finger represents RNAseH domain that removes RNA from hybridized DNA:RNA molecules during reverse transcription
63
Q

Do non-nucleoside RTIs inhibit reverse transcriptase of all retroviruses?

A

No, selectively inhibits HIV reverse transcriptase

64
Q

Do non-nucleoside RTIs inhibit mammalian DNA polymerases?

A

No

65
Q

Can NRTIs and NNRTIs be used together?

A
  • Yes, produce a synergistic effect
  • NRTIs mimic the normal nucleoside bases, so are technically incorporated into any enzyme that is functioning, no matter how slow; NNRTIs slow down the enzyme
66
Q

What is the main problem w/ NNRTIs? How can this be prevented?

A
  • Rapid emergence of resistance among HIV isolates, resulting from point mutations in gene coding of the enzyme
  • Prevented if NNRTI and NRTI are used together
67
Q

Which drugs are NNRTIs? Which ones must be used w/ at least 2 other anti-retroviral agents?

A
  • Nevirapine
  • Delavirdine *used w/ other agents
  • Efavirenz *used w/ other agents
68
Q

How are NNRTIs inactivated?

A

Hydroxylation

69
Q

Where do mutations in HIV-1 reverse transcriptase?

A
  • Residues in reverse transcriptase polymerase domain that are important in binding and incorporation of nucleotides
  • Side chains of residues that interact w/ next incoming nucleotide
  • Residues which interact w/ template strand to position it for base pairing w/ nucleotide; causes reduced incorporation of analogs
70
Q

What does HIV protease do?

A

Cleaves propeptides into enzymes that function in maturation and propagation of new virus

71
Q

What does HIV protease look like?

A

Symmetric dimer of 2 identical 99 amino acid subunits

72
Q

What are HIV protease inhibitors designed to mimic?

A
  • Transition state of hydrolysis at the active site

- Called analog inhibitors

73
Q

What is special about analog inhibitors?

A
  • Normal hydrolysis of peptides bonds proceed through an sp3-tetrahedral transition state
  • Analog inhibitors possess a pre-existing sp3 hybridized center that is drawn into active site and won’t be cleaved by the enzyme
74
Q

What is the goal of HIV protease inhibitors?

A

Arrest replication of virus at maturation step to prevent spread of infection

75
Q

What are side effects of protease inhibitors?

A
  • Dyslipidemia
  • Facial atrophy
  • Breast enlargement
  • Hyperglycemia
76
Q

Which drugs are first gen HIV protease inhibitors?

A
  • Saquinavir
  • Indinavir
  • Ritonavir, amprenavir, nelfinavir
77
Q

What is sp3 center for all the HIV protease inhibitors?

A

Phenylalanine-hydroxyl

78
Q

Which HIV protease inhibitors must be used w/ at least 2 other agents?

A

Ritonavir, amprenavir, and nelfinavir

79
Q

Why were second generation HIV protease inhibitors developed?

A

To inhibit HIV protease species that were resistant to first gen inhibitors (point mutations)

80
Q

Which drugs are second gen HIV protease inhibitors?

A
  • Lopinavir
  • Atazanivir
  • Tipranavir
  • Darunavir
81
Q

Which gen HIV protease inhibitors are used together? Why?

A
  • Lopinavir (2nd gen) and ritonavir (1st gen)

- Ritonavir inhibits lopinavir’s metabolism by CYP 3A4

82
Q

What is atazanivir always used w/?

A

Reverse transcriptase inhibitor

83
Q

What is special about tipranavir? What is the benefit to this?

A
  • Not a peptidomimetic (mimics peptides), but binds in active site like peptide-PI
  • Benefit = cross-resistance doesn’t develop
84
Q

What is the important portion of darunavir?

A

Bis-tetrahydrofuranyl moiety to form crucial hydrogen bond interactions in active site

85
Q

Does second gen HIV protease inhibitors still contain phenylalanine-hydroxyl sp3 center?

A

Yes, except tipranavir b/c not peptidomimetic

86
Q

What is the importance of the sp3 center for HIV protease inhibitors?

A

Acts as the intermediate for hydrolysis reaction

87
Q

What is the function of retroviral integrase? What do integrase inhibitors do?

A
  • Integrase enables its genetic material to be integrated into DNA of the infected cell
  • Inhibitors block strand transfer catalyzes by retroviral integrase enzyme
88
Q

Which drugs are integrase inhibitors?

A
  • Raltegravir

- Elvitegravir

89
Q

What is the primary metabolism of raltegravir?

A

Glucuronidation

90
Q

What does raltegravir do?

A

Binds to viral integrase and prevents DNA transfer function that inserts viral DNA into host DNA

91
Q

What must integrase inhibitors contain and why?

A
  • A dicarbonyl functional group for activity, metal binding, and strand transfer
  • A benzyl moiety to bind hydrophobic pocket
92
Q

How does HIV enter a host cell?

A
  • Glycoprotein gp120 mediates virus attachment to 2 membrane receptors (CD4 and chemokine co-receptor)
  • Bivalent interaction induces a conformational change in gp41 acting as an anchor, fusing viral envelope w/ host cell membrane
  • CCR5 (chemokine receptor 5) protein on surface of WBCs is chemokine co-receptor used by HIV for entry
93
Q

Which drug is a CCR5 receptor antagonist? What does it do? What test must be done first?

A
  • Maraviroc
  • Drug binds to CCR5, blocking HIV gp120 association and entry
  • HIV tropism test must be done to see if drug will be effective
94
Q

What are the other cell entry inhibitors?

A

Only maraviroc currently

95
Q

What is enfuvirtide? What does it do?

A
  • HIV fusion inhibitor
  • Binds to gp41 preventing creation of entry pore for capsid of the virus
  • Biomimetic peptide designed to mimic components of HIV-1 fusion machinery and displace them, preventing normal fusion
96
Q

When is enfuvirtide used?

A

For px where all other treatments have failed

Medicinal Chemistry - Winter (15 decks)

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