Anti-viral Agents

Question 1

Viral life cycle

Answer 1

Attachment or adsorption occurs between viral particle and host cell membrane. Pore forms in cell membrane, and viral particel or genetic information are released into host cell where replication of viral genome may commence.

Question 2

Antiviral agents must…

Answer 2

inhibit virus-specific events.
not cause toxicity to host
have a narrow spectrum of activity

Question 3

Tamiflu

Answer 3

Is indicated for treatment of uncomplicated acute illness due to influenza infection in patients 1 year or older who have been symptomatic for no more than 2 days.
Is also indicated in prophylaxis of influenza for patients of 1 yr and older.

Question 4

Relenza

Answer 4

Is indicated for treatment of uncomplicated acute illness due to influenza A and B virus in adults and paediatric patients 7 years of age and older who have been symptomatic for no more than 2 days.
Indicated for prophylaxis in adults and paediatric patients 5 years and older

Question 5

Amantadine (symmetrel)

Answer 5

Treatment of Influenza A:
100mg twice daily, initiate within 24-48 hours after onset of symptoms; discontinue as soon as poss based on clinical response.
Prophylaxis of influenza A:
100mg twice daily, continue through peak activity in community or throughout influenza season in patients who cant be vaccinated. Development of immunity following vaccination takes around 2 weeks.

Question 6

Rimantadine (flumadine)

Answer 6

Rimantadine HCL is for prophylaxis and treatment of illness caused by various strains of Influenza A in adults.
Successful deployment of this requires specific. accurate diagnosis of the infection and rapid intervention

Question 7

The problem of toxicity timeline:

50s
60s
70s
80s
90s

Answer 7

50s: first antivirals, thiosemicarbazones found to be active vs poxviruses. methisiazone appeared to be active vs smallpox but was very toxic
60s: selective toxicity thought to be impossible, intervention thought to cause too much damage to host.
Anti-herpesviruses were indentified but too toxic for systemic use.
70s: Development of safe oral systemic antivirals such as vidarabine which was active vs herpes simplex and had low toxicity which could be given topically or IV. Effective vs encephalitis
80s: Development of orally-administered antivirals such as aciclovir and penciclovir. Vidarabine was replaced. These drugs supressed genital herpes, they had low oral availability but encouraged prospects of further drugs. HIV emerged which was massive driver for anti-retrovirals. Valaciclovir replaces aciclovir for herpesvirus as it has a greater oral availability.
90s: First protease inhibitor, combined drug therapy against retroviruses.

Question 8

Importance of host immune system

Answer 8

Intact immune system vital for recovery from viruses
but not vital for anti-viral action.
Eg. Acyclovir v. effective in immunosupressed patients with herpes infection
Anti-retroviral therapy very effective in immunocompromised HIV patients.

Question 9

Life cycle stages common to all viruses

Answer 9

Infectious virus & transmission
attachment (adsorption)
penetration
uncoating: mRNA, transcription, DNA or RNA synthesis
Assembly
Release

Question 10

2 different types of action of Anti virals

Answer 10

Direct- bind/inhibit viral functions

Indirect- Inhibit host cell functions

Question 11

Virus molecular targets acted upon directly by anti-viral agents

Answer 11

Capsid proteins: agents that bind to picornavirus capsid and block capsid attachment to cell surface receptors.(Pleconaril vs rhinovirus)
Nucleic acids- nucleoside analogues that inhibit herpesviruses. Nucleosides and non-nucleosides analogues can inhibit HIV reverse transcriptase.
Ion-channel proteins are early influenza virus inhibitors that block an ion channel protein and inhibit particle disassembly.
Proteases: Blockers of HIV protease enzyme that inhibti processing of virus polypeptides.

Question 12

Cell functions modified in order to target viruses indirectly

Answer 12

Cyclin-dependent kinases are targets for inhibition of Herpes simplex virus
Apoptosis: Agents that promote apoptosis of virus-infected cells.
Immune system: Immune response modifiers that induce cytokine production. Imiquimod in HSV and HPV

Question 13

Imiquimod and Human Papilloma Virus

Answer 13

External genital warts caused by HPV
Imiquimod is anti-viral in form of Aldara cream
Aldara cream induces mRNA encoding cytokines including interferon at infection site.
HPVL1 mRNA and HPV DNA are significantly decreased following treatment.

Question 14

In Silico target identification:

Answer 14

Research conducted or produced by means of computer modelling or computer simulation.
Generates large number of possible candidates
Initial testing highlights a small number of candidates
Typically, a particular enzyme of pathway will be selected for development.
The first, or most promising member of a family of related chemical structures will generate the lead compound.

Question 15

Screening of lead compounds: 3 determinants

Answer 15

1. ) Inhibition of viral growth in tissue culture- determine conc of copmound that reduces virus titre by 50% (IC50).
2. ) Assessment of anti-viral activity in animal models: For example, testing of anti-herpesvirus drugs in rodents, particularly in latent infection.
3. ) Toxicity testing: Difficult to assess in tissue culture so other tests such as genetic damage tests and DNA repair tests are used

Question 16

Selective vs Therapeutic index: Ratios that compare toxicity with efficacy

Answer 16

1.) Selective index is generally based on tissue culture data. It is the ratio of….

50% toxic conc : 50% viral inhibitory conc

Ratio of 1:1 indicates very likely to be toxic in vivo

2.) Therapeutic index (based on in-vivo animal tests)

50% toxic conc : therapeutic dose

Value man remian theoretical for humans

Question 17

4 suitability factors of designed compounds;

Answer 17

Appropriate pharmological properties?
Lack of toxicity?
Available precursors for synthesis?
Cost-effective synthesis in large quantities?

Question 18

Evaluation of potential anti-viral agents: The clinical trials process

Answer 18

1a.) Initial safety and metabolism study in 4+ volunteers
1b.) expanded phase 1 study
1/2.) small combined study of safety + efficacy
2a.) In patients with target condition, 20+ people
2b.) larger number of patients, 100+
3.) large-scale safety + efficacy and comparison with placebo in 500-10,000 people.
NDA/MAA: application to sell and market drug
4.) post-market optimisations on formula, dosage, durations etc

Question 19

Rational drug design:

Answer 19

Finding new medicines based on the knowledge of a biological target.

Identify potential molecular targets- use viral genome sequence/protein structures
X-ray crystallography data for small organic compounds.
Protein database for polypeptides & polysaccharides.
In-silico molecular modelling