Pharm Topic 18: Antiviral Drugs

Front 1

5 Problems with antiviral therapy

Back 1

1) Viruses use host machinery
2) Viruses can go latent w/ out much activity
3) Acute infections may be unnoticeable and therefore arent treated early on.
4) Some viruses dont grow in tissue culture
5) Mutations arise @ rapid rate creating resistant pops.

Front 2

Palivizumab

Back 2

Drug used to treat RSV. Is a humanized mouse Ab specific to the viruses L glycoprotein

Front 3

3 general targets of HIV drugs

Back 3

1) Fusion inhibitors prevent viral entrance.
2) Reverse transcription can be targeted
3) Viral proteases can be targeted.

Front 4

Enfuvirtide

Back 4

HIV drug. Works by inhibiting fusion of the HIV envelope and the cellular plasma membrane.

Front 5

Selzentry

Back 5

HIV-1 Drug which prevents entry of virus into cell by being an antagonist of CCR5 which HIV uses to fuse its membrane with cells. Used when patients have become resistant to other drugs.

Front 6

Ways different ways drugs can target viruses

Back 6

1) Target a virus protein or function not found in host cells
2) Drug may inhibit host cell activity but is more effective act inhibiting the virus
3) A prodrug which must be activated by a viral enzyme, not a host enzyme
4) Drugs which target macromolecular biosynth. While not easy to be resisted, can really damage replicating cells of the host,

Front 7

Acyclovir

Back 7

Used for HSV1 (cold sores) and 2 (genital herps), Zoster.
Mech: Is a guanisine analog. Is only phosphorylated by viral thymidine kinase. Is incorporated into virus DNA and causes chain termination because it lacks 3' OH.

Front 8

Gancyclovir

Back 8

Used to treat CMV, especially in immunocompromised.
Mech: Is a guanisine analog. While cellular mechs can phosphorylate, Viral DNA pol has a much higher affinity for the drug than cellular DNA pol. Once incorporated into DNA, causes chain termination b/c it lacks 3' OH.

Front 9

Acyclovir and Gancyclovir resistance.

Back 9

Occurs when mutations destroy thymidine kinase, reduce thymidine kinases affinity for the drug, or when mutations of the viral polymerase reduce its sensitivity to the phosphorylated drug .

Front 10

Cidofovir

Back 10

ANP. Phosphorylated cytosine analog. Used to treat CMV and AIDS. Also effective against poxvirus.

Front 11

Adefovir dipivoxil

Back 11

ANP. Phosphorylated adenosine analog. Used to treat HBV.

Front 12

Tenofovir Disproxil Fumarate

Back 12

ANP. Phosphorylated adenosine analog. Used to treat HIV

Front 13

Acyclic Neucleoside Phosphonates

Back 13

(ex. Cidofovir, Adefovir, Tenofovir)
Are phosphorylated neucleoside analogs. Because of a lack of 3'OH, cause termination when incoorperated into DNA. Already phosphorylated so dont need thymidine kinase to put on first P. Work b/c Viral DNA pols have a higher affinity for the drugs than cellular DNA pols.

Front 14

Ribavirin

Back 14

Guanosine neucleotide analog. Used against RSV, influenza virus, poliovirus, and HCV (+ INF alpha). 4 possible mechs for HCV actions:
1) Inhibits IMP dehydrogenas > no GTP pools > no nucleic acid synth.
2) Substrate for RNA dependent RNA pol causing chain termination.
3) Incorporation acts as a mutagen for future replications.
4) Skews immune response towards Th-1 which is more effective against viruses.

Front 15

Strategies to minimize drug resistant strains

Back 15

1) Only use when needed
2) Use adequate amounts
3) Use combination therapy
4) Test isolates during treatment regime
5) Save some drugs for only certain diseases or replacement therapy.

Front 16

Phosphonoformic Acid

Back 16

Acts as a noncopetitive inhibitor of DNA pols by binding to the phosphate binding site. Works at a lower [] against viral pol but is too toxic to be used unless disease is life threatening.
Used for HIV, HBV and herpes.

Front 17

AZT

Back 17

Neucleoside analog of thymidine. Must be phosphorylated by cellular thymidine kinase. Works 2 ways. 1) HIV reverse transcriptase is 100 times more sensitive to AZT-PPP than cellular pols are. If incorporated, will cause chain termination. 2) Competes successfully for the TK, leading to thymidine-PPP depletion.
Has many side effects including BM suppression. Mutations of RT also cause resistance.

Front 18

Non-neucleotide RT inhibitors

Back 18

Bind allosterically inactivating the RT.

Front 19

HIV Protease inhibitors

Back 19

Peptidomimetic compounds which act by resembling the substrates for HIV proteases. This prevents the HIV polyprotein from being properly cleaved.

Front 20

Tipranavir

Back 20

A non-peptidomimetic inhibitor or HIV protease. Good for people whove become resistant to peptidomimetic drugs.

Front 21

Raltegravir

Back 21

Inhibits HIV integrase

Front 22

What are the drug targets to Influenza targeted against

Back 22

M2 and Neuraminidase

Front 23

Amantadine and Rimantadine

Back 23

Ion channel blockers; block M2. Used to treat influenza A. M2 is the proton channel allowing protons to enter the viral envelop while in the endosome. This decrease in pH allows hemagglutinin to cause fussion of endosome and envelop and release of viral RNA. If M2 is blocked, no RNA release.
No effect on B b/c different M2s, mutation of M2 = resistance.

Front 24

Oseltamivir and zanamivir

Back 24

Neuraminidase Inhibitors, known as plug drugs. Used to treat Influenza A and B. Hemagglutinin binds to sialic acid to cause initial membrane fusion for viral entrance. It also holds on to sialic acid when budding off after replication. The bud is released by neuraminidase which cleaves sialic acid. Blocking of this prevents bud release.

Front 25

Interferons

Back 25

Trigger the transcription of antiviral proteins which inhibit viral replication.

Front 26

Type 1 INFs

Back 26

INF alpha and Beta. Not viral specific. Reduce viral production. Are synthesized as part of the PAMP system: DS RNA binds to TLRs or to RNA helicases which activates signal transduction leading to INF alpha or beta production.

Front 27

PKR

Back 27

Protein Kinase R, Becomes activated following binding of dsRNA. It phosphorylates and inactivates eIF2 which is needed for mRNA translation. This stops both viral and cellular protein synth.

Front 28

2-5A synthetase.

Back 28

Becomes activated following binding dsRNA. 2-5A synthetase activates RNA endonuclease, RNase L, then degrades viral and cellular mRNA.