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KOKN01 - Medicinal chemistry > Dugga 3 - Antiviral > Flashcards

Dugga 3 - Antiviral Flashcards

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1
Q

What is zoonoses?

A

Viruses that can be transmitted to humans from animals or insects

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2
Q

What is SARS

A

Servere acute respiratory syndrome

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3
Q

Can viruses contain both RNA and DNA?

A

No, only either one. We can have DNA viruses and RNA viruses.

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4
Q

What defines a positive strand?

A

The base sequence of the RNA strand in the virus is identical to viral mRNA.

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5
Q

What defines a negative strand?

A

The base sequence of the RNA strand in the virus is comprementary to viral mRNA.

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6
Q

What is the purpose of the capsid?

A

Protect the nucleic acid. The capsid is made up out of protomers.

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7
Q

Nucleocapsid

A

Capsid + viral nucleic acid + sometimes RNA-dependent dNA polymeras or other enzymes crucial to its replication.

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8
Q

What is a virion?

A

The complete structure of the virus e.i the nucleocapsid + viral proteins and possible membranous layers

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9
Q

What is the size of a virion?

A

10-400 nm

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10
Q

Describe the stages of the life cycle of a virus

A
  • Adsorption: a molecule on the virion binds to a protein (glycoproteins) or carbohydrate present on the host cell.
  • Penetration and uncoating: injection of only the nucleic acid or the whole virion (endocytosis , fusion with lysosomes)
  • Replication and transcription. late or early viral genes, different pathways. Early genes take over the host cell and the viral DNA or RNA is synthesised.
  • Assembly of nucleocapsids: Late genes directs synthesis of capsid proteins that lead to self assembly of the capsid.
  • Viron release: naked virons are released by cell lysis. viruses with envelopes are usually released via budding
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11
Q

What is subunit vaccines?

A

Fragments of the virus is presented to our immune system, this fragment may display a characteristic antigene.

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12
Q

What makes it difficult to develop a virus for HIV?

A
  • Rapid gene mutation in HIV viruses results in constant changes to the amino acid composition og glycoproteins normally present on the viral surface
  • AIDS patients have a compromised immune system that vaccination is non effective
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13
Q

Why is the drug targets for viral infections fewer than for bacterial infections?

A

The virion/virus is hidden within the bodies own cells and uses their fucntions for reproduction/multiplication. Attacking the virus but not the bodies own cells i hard.

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14
Q

What are some early antiviral drugs?

A

Idoxuridine

Vidrarabine

Amantadine

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15
Q

What is the reason for the development of antiviral drugs?

A
  • AIDS pandemic
  • Viral genomic research: Increased understanding of viral infectious mechanisms
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16
Q

What cells does HIV target?

A

T-cells

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17
Q

What are characteristics of proteins that are good drug targets for antiviral drugs?

A
  • Important for life cycle, especially in the early stages
  • Little resemblance to human proteins
  • Common to a variety of different viruses
  • Have a specific region that is identical in its amino acid composition

-

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18
Q

Is it true that many drugs show broad activity against both DNA and RNA viruses?

A

No. Antiviral drugs used against DNA viruses and Antiviral drugs used against RNA viruses are quite different.

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19
Q

What is one inhibitor drug of viral DNA polymerase?

A

Aciclovir - prodrug, once phosphorylated (by thymidine kinase) in the body it mimics nucleotide triphosphates. Aciclovir triphosephate prevents DNA replication in two ways:

  1. Similar to the normal deoxyguanosine triphosphate bulding block but has an incomplete sugar. Act as an DNA polymerase inhibitor.
  2. Doesn’t inhibit DNA polymerase but as the sugar unit is incomplete and lacks a hydroxide group in position 3 the nucleic acid chain cannot be extended further making the Aciclovir a CHAIN TERMINATOR
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20
Q

Why is Aciclovir not inhibiting DNA polymerase in the host cell?

A
  • The phosphorylation of Aciclovir is much more favored in virion. The viral thymidine kinase is a hundred times more effective at converting Aciclovir into its monophosphate than host cell thymidine kinase. In the host cell Aciclovir is left as the prodrug.
  • Uptake of Aciclovir is selective in infected host cells.
  • Aciclovir triphosphate shows a 50fold affinity selective action against viral DNA polymerases compared to cellular.
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21
Q

What is a con of Aciclovir?

A

Poorly oral bioactivity.

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22
Q

How is valaciclovir better than aciclovir?

A

Better oral bioactivity. Aciclovir is transported from the gut via active transport. The L-valine in valaciclovir is probably better att interact with the transport proteins.

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23
Q

Some virions are immune to the strategy of aciclovir, why?

A

Lack viral thymidine kinases, the prodrug is never initially phosporylated.

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24
Q

How does cidofovir work?

A

Already has a ekvivalent phosphate group (active), phosphomethylene, cellular kinase can now phosphorylate further.

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25
Q

thymidine kinases is only required for the first of the phosphorylation of aciclovir, true or false?

A

true

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26
Q

Why is idoxuridine more toxic then aciclovir?

A

Becuase it is phosphorylated equally well by viral and cellular thymidine kinases ==> attacks both cells.

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27
Q

What is one inhibitor of DNA terminase complex?

A

Letermovir

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28
Q

What is the roles of DNA terminase complex?

A

Processing and packaging of viral DNA

  • catalyses concatemeres splitting
  • Assist translocation of the genome into the viral capsid
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29
Q

What is one inhibitor of kinases?

A
  • Maribavir
30
Q

What is one antisense therapy drug?

A

Fomivirsen - protein consiting of 21 nucleotides with a phosphonothioate backbone. The drug blocks the translation of viral RNA. Highly polar ==> intraviteral injection

31
Q

What are some antiviral drugs acting against hepatitis B?

A

The hepatitis B virus contains circular DNA. ==> DNA virus. The hepatit-B virus has an enzyme, DNA polymerase that has reverse transcriptase catalytic activity.

  • Interferon alfa
  • NRTI
  • Tenofovir (prodrug)
32
Q

Is HIV a RNA or DNA virus?

A

RNA

33
Q

What is the main targets in antiviral therapy against HIV?

A
  • Inhibit cell entry
  • Act against the viral enzymes:
    • reverse transcriptase
    • protease
    • integrase
34
Q

Inhibitors of viral reverse transcriptase consists of two classes. What differentiate them?

A

NRTI:
Inhibits reverse transcriptase (competative). This hinders viral RNA to be translated into viral DNA. Since host cells cant do reverse transcriptase this enzyme can be inhibitet and lead to major effects.

NNRTI: Non competitive, reversible inhibitors. Bind to a hydrophobic allosteric bidning site on the nucleoside reverse transcriptase. binding of NNRTI leads to an induced fit and lock the substrate binding site in an inactive conformation.

Sensitive to pan-class resistance mutation

35
Q

Why is reverse transcriptase a good drug target in anti HIV drugs?

A

The enzyme is unique to HIV. But it is a DNA polymerase so it bares similariteies with cellular DNA polymerases.

36
Q

NRTI requires cellular enzymes in order to be active?

A

HIV lacks the ability to produce viral kinase. This means that the virus needs cellular enzymes that can catalyse all three phosphorylations.

37
Q

What are some NRTI-drugs?

A

Zidovudine - chain terminator

Lamivudine - chain terminator

Didanosine

38
Q

What is activation of zidovudine?

A

zidovudine ==> zidovudine thriphosphate

39
Q

What are some NNRTI drugs?

A

Nevirpine

Delavirdine

Doravirine

40
Q

What are some protease inhibitors (PI)?

A

Saquinavir

Ritonavir
Lopinavir
Nelfinavir

41
Q

Are NRTI and IP both prodrugs?

A

No

42
Q

Why have PI low oral bioactivity?

Is NRTI better absorbed than IP in the gastronomical tact?

A

Most PI drugs are designed from peptide lead compunds, which have poor pharmacokinetic properties due to their high molecular weight, poor water solubility and susceptible peptide linkages, easy to metabolize (first pass metabolic effect is large).

Yes they are.

43
Q

What is an major side effect of PI?

A

Can inhibit cytochrome P450 isozyme. This may lead higher risk of to drug-drug interactions.

44
Q

Is there any pros with combinatoary therapy with IP and NRTI’s?

A

Yes, resuces the pace that resistance is developed.

45
Q

What does HIV protease enzymes do?

A

Catalyze the clevage of peptide bonds. The enzyme contains a aspartic acid (asp) in the active site.

HIV protease can cleave a peptide bond next to proline, this doesn’t uccur in mammalian cells.

HIV protease is symetrical. The enzyme have 8 possible binding sites for substrates.

Two asp 25 + H2O. Has a tetrahedral intermediate

46
Q

HIV protease inhibitors are often a certain kind of inhibitor, which type?

A

Transition state inhibitor. Mimics the tetrahedral intermediate. The drug consits of a transition state isostere.

47
Q

Why is renin inhibitor useful to study when devoloping PIs?

A
48
Q

PI are not targeting all the 8 binding sites in HIV protease, why not?

A

Would make the drug to bulky and poor oral bioactivity.

49
Q

Cell entry inhibitors

A

Enfuvirtide - fusion inhibitor. The drug matches the C-terminal end of the viral protein gp41 and formes a alfa-helix binding. This hinders the gp41 to anchor on the host cell surface and bring the virus close enough to the surface in order to fusion

Fostemsavir (prodrug for temsavir). The drug binds to gp120 and prevents it from interactig with host-cell CD4 membrane protein. The prodrug is needed since temsavir has low aqueous solubility.

-Ibalizumab Inhibitor of the host cell CD4 protein

  • MAraviroc. A CCR5 antagonist
50
Q

The viral glycoprotein gp120 is crucial to the adsorption of the HPV-1-virus since it is apart of the HIV-1-Envelope. How many gp120 subunits and how many gp41 subunits does it consist of?

A

gp120 - three
gp41- three

51
Q

Antiviral drugs acting against RNA viruses: Flu virus. What cells does the flu virus attack?

A

Epithelial cells of the upper respiratory tract

52
Q

What does the nucleocapsid of the flu virus contain?

A

(-) ssRNA + RNA polymerase

53
Q

What two glycoproteins does the membranous envelope contain?

A

NA and HA. Spike like objects that project about 10 nm from the surface.

NA helps the virus to negotiate a layer of protective mucus. NA cleaves sialic acid from the glycoproteins and glycolipids ==> this degrades the mucus layer and allows the virus to reach the epithelial cells.

HA also recognize the sialic acid but doesn’t cleaves it, the HA binds to it.

54
Q

Receptor mediated endocytosis

A
55
Q

Why is a balance of NA and HA important?

A

If NA is too active, it would hinder infection of the cell by destrouing the receptors recognized by HA.

If NA is too inactive, the newly formed virons would remain adsorbed to the host cell after budding preventing infection spread to other cells.

56
Q

Can HA and NA act as antigenes?

A

yes, since they are on the outside of the virus. But they are very prone to antigenic variation due to error prone RNA polymerase.

57
Q

How many groups of flu virus are there?

A

Three: A, B, C

A - prone to antigenic variation

58
Q

What is antigenic drift?

A

A small change in variation of NA and HA. This is comon in flu-A.

59
Q

What is antigenic shift?

A

A large change in variation of NA and HA. lead to epidemic and pandemics.

60
Q

What is adamantanes?

A

Ion channel disrupters, anti fluvirus drugs. Blocks matrix protein (M2). Blocking the ion channels
hinders the virus to buffer for more basic environment. HA needs acidic environment to fuse membranes with the endosome. Blocking the ion channel will inhibit penetration of host cell and uncoating of the virus.

Amantadine

Rimantadine

61
Q

Nuraminidase inhibitors (NA)

A
62
Q

How is sialic acid interacting/bound to the active of NA?

A
  • Hydrogen bonding
  • Ionic interactions between the carboxylate ion of the sialic acid and the arginine residues.
  • Glycerol side chain ==> glutamate and two waters
  • Hydroxyl group ==> hydrogenbonding
  • Acetamido substituent ==> fits a hydrophobic pocket
63
Q

What type of inhibitors targets NA?

A

TS-inhibitors ex: NEu5Ac2en

The transition state of a NA and sialic acid reaction is planar in C2 trigonal center.

64
Q

What way is relenza developed?

A

Adding ionic positive interactions, introducing guanidium ion. Developed using GRID

65
Q

What is an disadvantage of NEu5Ac2en-like drugs (Zanamivir)?

A

Their glycerol side chain is polar and can’t be removed since it has an importan role in binding to NA. It can’t be removed but replaced by carboxamide side chain ==> new type of TS-analog inhibitors 6-carboxamides

66
Q

Tamiflu development

A

Started from Neu5Ac2en

  1. Dihydropyran oxygen removed.
  2. Make it more like the TS-state
  3. Introducing hydroxyl substiuent in place of the glycerol side chain ==> inductive e withdrawing effect ==> removed its electron density ==> less polar + we now can make ether analogues
67
Q

What was the optimal ether side chain when alkoxy analogues of NEu5Ac2en were studied?

A

Pentyloxy side chain

68
Q

Is GS 4071 a prodrug of Tamiflu?

A

No, Tamiflu is a prodrug of GS4071

69
Q

What type of viruses cause colds?

A

Rhinovirus (HRV)

70
Q

Broad-spectrum antiviral agents

A
71
Q

What is K103N mutation at the allosteric binding site of non-nucleoside reverse transcriptase inhibitor (HIV-drug)?

A

pan-class resistance mutation.

The mutation consists of switching Lys-103 against asparagine

KOKN01 - Medicinal chemistry (12 decks)

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