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Thera VIII > 07 Anti-Viral Drugs Duncan > Flashcards

07 Anti-Viral Drugs Duncan Flashcards

1
Q

What is the specificity of Anti-Viral agents?

A

Viral targets tend to be similar to human proteins. Therefore, antiviral agents must be precisely designed to bind to viral protein preferentially

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2
Q

What are the nucleic acid building block bases?

A

Purines (Adenine, Guanine). Pyrimidines (Thymine, Cytosine)

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3
Q

What does a nucleoside need to go through before being incorporated into the growing DNA chain?

A

Nucleoside gets 3 phosphates added on through a kinase. Only then can it bind with DNA polymerase and be incorporated into the growing DNA chain

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4
Q

What are the three modes of inhibition of Anti-Viral Nucleoside Analogues?

A

1) Block phosphorylation (by inhibiting Kinase). 2a) Competitively inhibit binding to DNA polymerase. 2b) Inactivate DNA polymerase. 3) Chain termination

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5
Q

What are two aspects of selectivity involving the DNA polymerase interaction?

A

1) Nucleosides must be converted to the triphosphate form before they interact with DNA polymerase. The initial phosphorylation is catalyzed by a viral kinase that greatly prefers the AVDrug. 2) The AVDrug-TP has a much higher affinity for DNA polymerase

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6
Q

What are some of the Nucleoside Analogues used that use replication as their target?

A

Acyclovir (prodrug: Valacyclovir). Penciclovir (prodrug: Famciclovir). Ganciclovir

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7
Q

Which nucleoside analogues have similar structures to Guanosine?

A

Acyclovir. Penciclovir. Ganciclovir

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8
Q

What is the rationale for using the prodrug of Acyclovir (Valacyclovir)?

A

The Valine (VALacyclovir) promotes uptake by intestinal PepT1 transporter. This greatly increases oral BA, with increased AUC, decreased dosing frequency. Prodrug rapidly converted to Acyclovir once absorbed

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9
Q

What are the general characteristics of Acyclovir and the similar Nucleoside Analogues?

A

All primarily for Herpes Viruses (HV). Purine analogues, resembling Guanosine. Recognized by HV Thymidine Kinase (preferentially). Converted to triphosphate. Inhibit DNA polymerase, and chain terminator. Ganciclovir is primarily used for CMV. Cidofovir primarily used for AIDS CMV retinitis

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10
Q

What is the MOA of Acyclovir?

A

3 sites of inhibition: 1) Competitive inhibition of DNA Polymerase. 2) Chain termination. 3) Suicide inhibition - permanent binding of DNA polymerase to growing chain

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11
Q

What is unique about Cidofovir?

A

Comes in a phosphate form, doesn’t require viral Kinase phosphorylation for activity

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12
Q

What is the sensitivity to Acyclovir and the similar Nucleoside Analogues?

A

Herpes viruses are sensitive based on virally-encoded thymidine kinase (Acyclovir binds TK 100-200x thymidine). Resistance arises d/t: Loss of virally encoded TK (most common), Loss of preference for Acyclovir over Thymidine, Altered DNA polymerase

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13
Q

Which Nucleoside Analogues act as Thymidine Analogues?

A

Idoxuridine. Trifluridine

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14
Q

What are the general characteristics of Idoxuridine and Trifluridine (Nucleoside Analogues)?

A

All primarily for Herpes viruses. Pyrimidine analogues, resembling thymidine. Recognized by Thymidine Kinase. Converted to triphosphate. DNA made with Idox or TF is faulty because it lacks the thymidine methyl; no growth

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15
Q

What are the Arabinose-Based Agents (Nucleoside Analogues)?

A

Vidarabine (similar to Adenosine). Cytarabine (similar to Cytosine). Sorivudine (similar to thymadine)

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16
Q

What are the general charactersitics of Arabinose-Based Anti-Virals?

A

All primiarly for Herpes viruses. Converted to triphosphates. Preferentially utilized (~40x). Inhibit DNA polymerase

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17
Q

What is the Pyrophosphate analogue used for Replication Inhibition?

A

Foscarnet Sodium. Blocks pyrophosphate binding. Blocks pyrophosphate cleavage. Associates with a DNA Polymerase pyrophosphate binding site

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18
Q

What are the Dideoxynucleoside Analogues?

A

Zidovudine (AZT). Didanosine. Zalcitabine. Stavudine. Abacavir. Lamivudine. Emtricitabine

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19
Q

What are Dideoxynucleoside Analogues primarily used for?

A

Primarily against Retrovirus (e.g. HIV)

20
Q

What is the MOA of Dideoxynucleoside Analogues?

A

1) Inhibits cellular Thymidine kinase (Retroviruses do not encode their own TK). 2) Direct RT DNA Polymerase inhibition. 3) Chain terminators when incorporated

21
Q

What is the resistance to Dideoxynucleoside Analogues?

A

Mutations in RT. Multiple mutations required to achieve high level Resistance. Resistance develops frequently; months to years

22
Q

What are some Anti-Hepatitis B agents?

A

Adefovir Dipivoxil. Lamivudine. Other HIV RT inhibitors (other cyclovirs)

23
Q

What is the MOA of Adefovir?

A

2 sites of inhibition: 1) Competitive inhibition of RT. 2) Chain termination

24
Q

How do Non-Nucleoside RT Inhibitors (NNTRI) work?

A

Utilize selective binding site on RT. NNRTI binding to its site induces a conformational change in the RT active site (i.e. it is an allosteric inhibitor)

25
Q

What is resistance like to NNTRI?

A

Resistance develops relatively quickly d/t mutations in binding site. Examples: Nevirapine, Loviride, Efavirenz

26
Q

What is a “Second Generation” NNRTI?

A

Etravirine. Retains activity against RT that has developed mutations conferring resistance to Efavirenz, Nevirapine. Regulates uncoating

27
Q

What are some Anti-Influenza Agents used?

A

Ribavirin (ribose purine analogue). Amantidine (high resistance). Relenza (Zanamivir). Tamiflu (Oseltamivir)

28
Q

What are the general characteristics of Ribavirin?

A

Primarily for RSV and HCV (originally for Influenza). Converted to triphosphates. Inhibits RNA Polymerase (Flu). Also inhibits viral DNA Polymerase (Herpes)

29
Q

What are the general characteristics of Amantidine (Rimantidine)?

A

Blocks M2 protein activity: Ion channel in virion particle, Regulates pH (H ion entry), Regulates uncoating, Ubiquitous resistance. Unique to Influenza A

30
Q

What are the Anti-Flu Neuraminidase Inhibitors?

A

Oseltamivir and Zanamivir

31
Q

What does the Influenza Life Cycle look like?

A

Influenza virus binds to Sialic Acid (a Sugar, not protein). Virus goes through internalization, infects cells, then buds new viruses with the help of Neuraminidase

32
Q

How does Rhinovirus work?

A

Rhinovirus binds to its cell surface receptor at the junction of the VP1, VP2, VP3 proteins. Hydrophobic canyon at base. Conserved feature among varieties of Rhinovirus

33
Q

What is Pleconaril, and how does it work?

A

Anti-Rhinovirus Agent. Binds deep in the cavern of the virus (VP1, VP2, VP3), preventing attachment to receptor

34
Q

What are Interferons?

A

Synthesized and secreted by infected human cells (endocrine, autocrine, paracrine effects). Not “self” protective, but altruistic. Bind to cell surface receptor. Induce new proteins to be synthesized (PKR (kinase blocks translation initiation) and RNaseL (nuclease degrades mRNA), ADAR, 2,5AS)

35
Q

What does 2,5AS do?

A

Destroys viral RNA

36
Q

What does PKR and ADAR do?

A

Anti-Viral proteins, PKR destroys viral mRNA

37
Q

Why do Life-Cycle Based agents tend to be virus-type specific?

A

Because each virus has different proteins carrying out its life cycle functions

38
Q

What are the general steps in the viral life cycle?

A

Binding to human cell surface protein. Entry into the cell. Uncoating. Replication (Retroviruses). Transcription. Translation. Protein processing. Exit from the cell (budding)

39
Q

What are some methods to prevent virus binding?

A

Antibody to GP120. Soluble CD4 (binds GP120 without being attached to a cell). Antibody to CD4

40
Q

What is Maraviroc and how does it work?

A

Approved Anti-HIV Agent. Blocks binding of GP120 to CCR5. Oral agent. Not active against HIV types using CXCR4

41
Q

What is Enfuvirtide (Fuzeon) and how does it work?

A

Approved Anti-HIV Agent. Blocks membrane fusion mediated by GP41. Injectable 36 amino acid peptide

42
Q

How do Integrase Inhibitors work?

A

Target a uniquely viral biochemical event (nuclear integration of ds viral DNA into host (human) chromosomes)

43
Q

What is Raltegravir?

A

Integrase inhibitor

44
Q

Why is blocking transcription important for anti-viral therapy?

A

Specific viral mRNA transcription can requires DNA element-specific transcription factors (NF-kB for HIV). Block transcription –> block infection

45
Q

What do the HIV Protease Inhibitor structures feature?

A

Peptide bonds, and amino acids or partial AA structures

46
Q

What is unique about Ritonavir?

A

Giving a small dose of Ritonavir w/ another HIV Protease Inhibitor will “boost” them by decreasing their liver metabolism

Thera VIII (24 decks)

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