Antivirals

Question 1

There are no ___ antiviral drugs

Answer 1

There are no “broad spectrum” antiviral drugs

Question 2

4 Antiviral MOA

Answer 2

1. Inhibit viral nucleic acid synthesis
2. Inhibit production or function of essential viral proteins
3. Interfere with viral entry into cells
4. Increased activity of the immune system with interferons

Question 3

Interferons

Answer 3

Very toxic

pegylation/conjugation with polyethylene glycol extends half life

Question 4

Nucleosides

Answer 4

Nitrogen containing ring structure
(purines, pyramidines)

Sugar
(ribose, 2’deoxyribose)

Question 5

Nucleoside Kinases

Answer 5

Phosphorylate the sugar at 5’

Different enzymes work on the 2nd and 3rd 5’ phosphorylation

becomes nucleotide and tri-nucleotides are used for DNA, RNA synthesis

Question 6

Polymerases do what?

Answer 6

Catalyze the 5’ to 3’ addition of a trinucleotide to a chain

Then there’s liberation of pyrophosphate. Foscarnet is a pyrophosphate analog and has antiviral activity - very nephrotoxic

Question 7

Nucleotide: ___

Answer 7

phosphorylated

Question 8

Nucleoside Analogs

Answer 8

1st attempt - modify purine/pyramidine or replace ribose with arabinose

Modification of ribose or deoxyribose is better tolerated

Question 9

If no 3’ hydroxyl group, ____

Answer 9

stops chain elongation. Cannot add the triphosphates

Question 10

Nucleoside Analog Targets

Answer 10

Kinases that catalyze the initial 5’ phosphorylation

mutated kinases can be bypassed with 5’ mononucleotides

Question 11

Antiviral Nucleotides

Answer 11

Cidofovir (IV, Nephrotoxic)

nucleotides ionized at body pH - cannot diffuse (poor PO, limited cell penetration)

Question 12

Nucleoside, Nucleotide Pharmacology

Answer 12

Most are orally effective
Prodrugs may increase blood levels
Enter the cell by nucleoside transporter or passive diffusion
Excreted in urine
Not metabolized
Plasma T1/2 is short but Nucleotides cannot diffuse out once in the cell and that can prolong the effect

Question 13

Nucleoside, Nucleotide Adverse Effects

Answer 13

Acyclic - low incidence

Dideoxy - myopathy, neuropathy, myelosuppression, lactic acidosis, steatosis, pancreatitis

Question 14

Summary Nucleoside Strategy

Answer 14

Some of the analogs are better substrates for viral enzymes than the natural ones - preferential utilization in viral infected cells

If analogs are poor substrates, incorporation is low

Question 15

Protease Inhibitors

Answer 15

Prevent proteolytic cleavage of essential viral proteins into mature, active forms.
Unreliable as sole therapy; rapid resistance
Use in combination chemotherapy with a nucleoside analog and/or other anti-virals

Question 16

Saquinavir

Answer 16

Saquinavir was the first protease inhibitor developed

Complex chemical structures; based on structure of HIV protein hydrolyzed

Question 17

Protease Inhibitors - Gen pharm

Answer 17

Heavy drugs but orally effective
Bio-availability affected by food
Some require taking with fatty meals for best absorption
Metabolized by CYP450 enzymes (usually CYP3A4)
May affect metabolism of other drugs

Question 18

Boosting therapy –

Answer 18

Boosting therapy – CYP450 inhibitor to keep it in circulation longer so its not getting metabolized as quickly.

The PIs are substrates for the CYP 450 enzymes
“Boosters” are CYP inhibitors
Prolong PI presence in the body
Ritonavir - Weak PI, but a strong P-450 inhibitor
Cobicistat is newer; more widely used

Question 19

Adverse Effects of Protease Inhibitors

Answer 19

GI symptoms (nausea, diarrhea)
Abnormalities in lipid metabolism
Fat redistribution (“buffalo hump”)
Insulin resistance and ‘metabolic syndrome’
Potentially hepatotoxic

Because of adverse effects, PIs have largely been replaced by safer, more effective agents.

Question 20

Anti-Herpes Drugs

Acyclovir

Answer 20

Acyclovir
Targets Herpes thymidine kinase
Acyclovir triphosphate competes with GTP for polymerase
Terminates chain elongation if added to DNA
Oral - only 12-20%

Question 21

Other Drugs Used for Herpes and Varicella

Valacyclovir

Answer 21

Valacyclovir
“Pro-drug” of acyclovir (valine ester)
Rapidly hydrolyzed in bloodstream to release acyclovir
More than doubles the bioavailability of acyclovir

Question 22

Anti-Cytomegalovirus (CMV) Nucleoside Drugs

_____

Answer 22

Ganciclovir is the prototype
CMV kinase has high affinity

If resistant: Cidofovir, Foscarnet (both nephrotoxic

Question 23

Letermovir

Answer 23

Unique MOA: Inhibition of a “CVM terminase complex”

Current indication: Prophylaxis in CMV-seropositive patients undergoing stem cell transplants

Question 24

Flu - Neuraminidase Inhibitors

Answer 24

Oseltamivir
Tamiflu®
Oral pro-drug
Indicated for early sx of flu
Oseltamivir has been approved for prophylaxis
Not to replace immunization
Potential value in avian/swine flu epidemics

Question 25

*HIV - Combo Therapy Strategy (want combo to target DIFFERENT bases)

Answer 25

Initial combination chemotherapy with 3 or more agents: An “integrase inhibitor” 2 or more nucleoside reverse transcriptase inhibitors Modify agents if viral load increases Add agents with other mechanisms for resistant infections NNRTIs, PIs, entry inhibitors

Question 26

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) HIV

Answer 26

Zidovudine* Azidothymidine (AZT, ZDV) Prototype Phosphorylated intracellularly AZT triphosphate competes with thymidine triphosphate for reverse transcriptase binding

Question 27

Other Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Answer 27

Tenofovir Acyclic AMP analog A mononucleotide Tenofovir Disoproxil Fumarate - orally effective acyclic mononucleotide On WHO list of essential drugs Considered safe to use in pregnancy

Question 28

Class-Related Toxicities of NRTIs

Answer 28

``` GI intolerance Peripheral neuropathy Lactic acidosis, pancreatitis Bone marrow suppression Lipotrophy (stavudine, zidovudine) Renal toxicity (tenofovir) Aging-associated diseases (cancer, cardiovascular disease) ```

Question 29

Properties of NNRTIs

Answer 29

Unreliable as sole therapy Used in combination with NRTIs, INSTIs, PIs Metabolized by CYP450 enzymes “Boosting agents” used with some Class toxicities Serious rashes, hepatotoxicity, dyslipidemias

Question 30

Integrase Strand Transfer Inhibitors (INSTIs)

Answer 30

“Integrase inhibitors” block insertion of viral DNA into the host cell genome Orally effective Mild GI, CNS effects are major adverse reactions

Question 31

Agents That Block HIV Entry Into Cells

Answer 31

MOAs: Prevents viral entry into CD4+ cells Only for “CCR5-tropic viruses” Monoclonal antibody against HIV-CD4 complex

Question 32

Hepatitis B Vaccine Available

Answer 32

A DNA virus Replicates through an RNA intermediate and a polymerase with reverse transcriptase activity Recommended therapy: An NRTI Pegylated interferon may be added

Question 33

Hepatitis C Virus (HCV)

Answer 33

``` RNA virus A leading cause of liver cancer Seven known genotypes of HCV Genotype 1 most common in USA Other genotypes respond variably to antiviral therapies ```

Question 34

Ribavirin

Answer 34

Anti-HCV nucleoside analog Hemolytic anemia – most serious toxicity ``` Genotoxic and embryotoxic in all species FDA pregnancy class X (2 forms of BC) ``` Prior to 2011, standard of care was ribavirin plus pegylated interferon

Question 35

Direct-Acting Antivirals (DAAs)(No bioactivation needed)

Answer 35

HCV genome codes for a peptide that is cleaved into ten proteins Two are structural and appear in the viral envelope Some of the non-structural (NS) proteins are targets for drugs May possess a high degree of selective toxicity – relatively well-tolerated by patients Similar properties as anti-HIV PIs Dramatically improved response to ribavirin plus interferon But added significant PI adverse effects

Question 36

Newer HCV Antivirals Introduced After 2011

Answer 36

Sofosbuvir - NS5B Polymerase Inhibitors

Question 37

Current Experience with DAAs

Answer 37

``` SVR > 90% Ribavirin may be added for serious infections All HCV genotypes can be treated Orally effective Generally well-tolerated But some new problems: Re-activation of HBV inf. Many clinically significant drug interactions Serious liver injury Prohibitive cost ```

Question 38

Smallpox

Answer 38

Tecovirimat (Tpoxx®) Safety demonstrated in healthy human volunteers Stockpiled in case of bioterrorism involving smallpox

Question 39

Summary - Herpes, Varicella

Answer 39

Acyclovir, Valacyclovir

Question 40

Summary - Cytomegalovirus

Answer 40

Gancyclovir

Question 41

Summary - Flu

Answer 41

Oseltamivir (Neuraminidase inhibitor) sx relief.

Question 42

Summary - HIV

Answer 42

``` NRTI - Zidovudine, Tenofovir PIs NNRTI IH Entry Inhibitors ```

Question 43

Summary - Hepatitis

Answer 43

B - Reverse Transcriptase (adofovir, tenofovir) C - Combo of direct aciting antivirals, NS5B protease inhibitors (Sofosbuvir)

Question 44

Summary - Topical

Answer 44

Skin - Acyclovir, penciclovir, docosanol Ophthalmic - Gancyclovir, Trifluridine