lec 6- Antiviral Flashcards
1
Q
Viral infection and replication
A
- Glycoprotein envelope- protecting envelope
- mRNA- inhibit polymer synthesis
- Synthesis of structural and non-structural proteins- inhibit polymer synthesis
- Viral assembly
- Interfere with release of new virus as well
- ENZYME inhibitors
2
Q
Challenges to the development of effective antiviral agents
A
- A myriad number of agents
- Need knowledge of replication at a molecular level to define targets
- Which enzyme is involved in which step: design of enzyme inhibitors
- Problem: viruses as intracellular parasites (inside the body) make targeting more difficult to avoid host toxicity
- Lack of culture systems for some agents hinders development, assay development
- High through-put screening plus ‘rational’ drug design is both labours intensive and expensive
3
Q
Anti-viral assays
A
- In vivo for cancer assay test molecule in mice with even the ‘right’ human cells in nude mice (allograft, xenograft study)
- Antiviral- test in which animal, problem virus is specific to organism
- In vitro, cannot be tested in an agar plate as antibiotics, need cell culture
- Infect cancer cells with virus, cells killed by virus or test drug
- Seperate Cytotoxic activity from antiviral activity
- Saftey issues, expensive lab
4
Q
MOA 1: work on uncoating of influenza virus
A
- Blocking the removal of the protective glycoprotein coating
- Envelope binds to the receptor on a human cell, causing glycoproteins to fuse with the membrane this is what allows the viral genome to enter into the infected cell
5
Q
Amantadine and Rimantadine
A
- Tricyclic amines
- Active vs influenza A ONLY
- High selectivity is a problem
- The problem to build up working concentrations
- Mechanism of action
- Uncoating, coat with glycoproteins = sugar + proteins
- PK pharmacokinetics
- Orally bioavailable
- Amantadine: renal excretion
- Rimantadine: hepatic metabolism and renal excretion (Main difference)
- Major toxicity
- Neurotoxicity: amantadine > Rimantadine (main difference)
- Useful for treatment and prophylaxis of influenza A infections
- Resistance mediated by mutations
6
Q
Influenza
A
- Influenza virus => Absorption => Endocytosis => Endosomal vesicle => Uncoating => RNA replication => Synthesis of viral proteins => Assembly => Budding => Release
- RNA replication => new RNA => Assembly
7
Q
Neuraminidase Inhibitors: Zanamivir and Oseltamivir (Tamiflu)
MOA (mechanism of action) 2 release of virus
A
- Active vs Influenza A and B
- Binds to viral neuraminidase, enzyme inhibitor
- Mechanism of action- Neuraminidase inhibitors
- Inhibition of viral neuraminidase
- Neuraminidase catalyzes the cleavage of terminal sialic acid (sugar acid) residues attached to glycoproteins and glycolipids, a process necessary for release of virus from host cell surfaces
- Oseltamivir is an ester prodrug, ethyl ester
8
Q
Structural similarities of sialic acid Zanamavir and Oseltamivir III
A
9
Q
From sialic acid to tamiflu
A
- Sialic acid, sugar, compare glucose very similar, glucose acid
- Amino sugar (glucosamine)
- Biosphere O replaced by carbon
- Zanamivir; pyran acid- very closely related to the sialic acid= enzyme inhibitor
- Oseltamivir; a prodrug, ethyl ester, no pyran, no sugar, more stable
- A good example of drug design, clinically better than placebo
10
Q
Zanamivir and oseltamivir
A
- PK- Zanamavir (Oral inhalation)
- Oseltamivir, Tamiflu
- Orally bioavailabile
- Converted from ester prodrug to active form
- Renally excreted
- Toxicities
- Reactive airway disease by Zanamavir
- Nausea and vomiting for oseltamivir, risk benefit ratio
11
Q
Zanamivir and Oseltamivir- Indications and resistance
A
- Indications
- Treatment of influenza A and B within 24-48 hours of symptom onset
- Prophylaxis
- Neither drug interferes with Ab response to influenza vaccination
- Resistance
- Reports appearing
- Incidence may be increasing
12
Q
Anti-Herpesvirus Agents
A
- Famciclovir
- Idoxuridine
- Ganciclovir
- Trifluridine
- Sugars, look like ribose?
- Enzyme inhibitor
- You either modify sugar or base (NOT BOTH)
13
Q
Anti-herpes Agents
A
- Idoxuridine: Idoxuridine, uridine containing iodine
- Trifluridine: Uridine base with a trifluoro methyl group- pyrimidine system, DNA can’t continue to build
- Both agents have ribose, original sugar moiety not modified
- Ganciclovir, base OK, sugar ring opened, clinical drug design, glycol mimics sugar
14
Q
Synthetic antiviral agents
A
- Heterocyclic template, base
- And a sugar, in particular, the simplified sugar molecule
- Acyclovir, right, sugar replaced by glycol side chain (used because it is very cheap), caffeine synthesis combined with sugar
- Principle antiviral design: modified base or simplified sugar molecule
15
Q
DNA basics
A
- A-T bases = 2 hydrogen bonds
- C-G bases = 3 hydrogen bonds
16
Q
A nucleotide consists of a nitrogen-containing base, a ribose or de-oxyribose sugar a phosphate group
A
- Chemical targets
- Modified base
- Wrong base
- Enzyme inhibitors
17
Q
Aciclovir mechanism of action
Synthesis of DNA/RNA polymer
A
- Aciclovir is phosphorylated by herpes virus thymidine kinase with ATP (single phosphate group placed on)
- This phosphorylated Aciclovir is further phosphorylated (addition of 2 more phosphate groups) by ATP and cellular kinases
- This tri-phosphorylated aciclovir is 10X more efficient with herpes virus DNA polymerase
20
Q
Overview- Action of some important antivirals
A
- Amantadine blocks Uncoating
- Release oseltamivir blocks neuraminidase
- Synthesis foscarnet block DNA polymerase in DNA virus
- AZT blocks reverse transcriptase in RNA viruses
