Antivirals Flashcards
What is a mM?
millimolar
10^-3
What is a um?
micromolar
10^-6
What is a nm?
nanomolar
10^-9
What are the 4 properties of a good antiviral?
- good selective index
- specificity and potency in vitro
- good therapeutic index
- good oral bioavailability
What are 4 things pharmacokinetics are affected by?
Absorption - how well does the drug get into circulation
Distribution - does it go to the right tissues?
Metabolism - how quickly is it broken down?
Excretion - how quickly is it excreted from the body?
How are new compounds discovered?
- high throughput screening
- molecular modelling
- structure/activity relationships
Describe Phase I clinical trials
Small no of healthy volunteers (10-50)
Single small dose increasing to higher multiple doses
Looking for adverse effects and pharmacokinetics
Describe Phase II clinical trials
Small no of patients (50-100)
IIa - confirm metabolism is the same as healthy volunteers.
IIb - campre with placebo for efficacy. Usually double blinded
Describe Phase III clinical trials
Large nos of patients (1000s)
Randomised double-blind trial vs placebo and existing treatments.
Spectrum of therapeutic benefit:risk
Describe Phase IV clinical trials
After approval for marketing
Large scaler, broader patient pop
Monitored for long term effectiveness/side effects
Further studies may test the drug in new age groups of patient types and in new formulations.
What are the 4 types of herpesviruses?
HSV - cold sores, genital herpes
VZV - chicken pox, shingles
EBV - glandular fever
CMV - asymptomatic in adults but life-threatening to ICs and infants
What did the first antivirals target?
DNA replication in herpesvirus
Name 2 nucleoside analogues
Thymidine
Idoxuridine
What is an issue with idoxuridine?
Idoxuridine triphosphate can also be incorporated into DNA by host cell DNA Pol
Cannot be used as systemic antivirals
What was the first systemic antiviral?
Adenosine.
What is an issue with adenosine
Lower toxicity
Name 3 guanosine analogues
Aciclovir
Ganciclovir
Penciclovir
What are 2 pros of aciclovir?
Highly selective
Low toxicity
What is aciclovir effective against?
HSV, VZV, EBV but not CMV
What is ganciclovir used to treat?
CMV
What is a pro and a con of penciclovir?
Less selective than aciclovir/ganciclovir because it can be converted into its triphosphate form by cellular enzymes to.
More stable than aciclovir so persists int he body for longer
Describe the bioavailability of the guanosine analogues
Poor by oral uptake (10-20%)
How can the bioavailability of guanosine analogues be improved
Given as a valine ester e.g. valaciclovir or a diacetyl ester e.g. famciclovir.
What is a prodrug
Metabolised in vivo to the active form e.g. valaciclovir or famciclovir
What is foscarnet
PPi analogue.
What is foscarnet active against
HSV, VZV, CMV.
Poxviruses, HBV, HIV
What is sorivudine
Bromide modified uracil
Fatal interaction with anti-cancer drug 5-fluorouracil
What is fialuridine
Fluorine modified idoxuridine
Phase II trails - delayed toxicity but not toxicity in animal models
When can therapy be applied for influenza?
Prophylactically
Immediately on onset on symptoms
What are the 2 classes of influenza drugs?
Adamantines - flu A only
Neuroaminidase inhibitors - flu A and B
Give 2 examples of neuroaminidase inhibitors
Zanamivir and Oseltamivir
What is ribavirin
Broad spectrum anti-RNA virus compound
Ribose neucleoside analogue
Used against children with RSV, viral haemorrhagic fevers, flaviviruses
What are type I IFNs used to treat?
HBV and HCV with ribavirin
What was the first anti HIV drug?
Zidovudine (AZT)
NRTI
Name a next generation NRTI
Lamivudine
Name a NNRT
Nevirapine
Where is the HIV protease cleavage site?
Between the Phe-Pro.
What is the first protease inhibitor?
Saquinovir
Name 2 protease inhibitors
Saquinovir
Ritonavir
What is the first integrase inhinitor
Raltegravir
What is the first entry inhibitor?
Enfuvirtide
What is a con of Enfuvirtide
Very expensive
Difficult regimen, self infection
98% skin reactions
Name a fusion/cell entry inhibitor
Maraviroc - blocks CCR5
Name a maturation inhibitor
Bevirimat
What is HAART
Highly active antiretroviral therapy
2NRTIs + 1NNRTI
2NRTIs + 1PI
What does therapy depend on?
Country Age T cell count Viral RNA level Side effects
What are ribozymes?
RNA enzymes, designed to bind and cleave viral RNA targets
What do ribozymes target in HIV?
Tat, Rev, U5 region of HIV RNA
What do Antisense RNAs in HIV?
Env mRNA, U5 region of HIV RNA
What does RNAi target?
Tat, Rev, U5 region
What do RNA decoys target?
TAR and RRE sequester Tat and Rev
How can we combat resistance caused by RNA drugs?
Knock down levels of cellular proteins - CCR5
Use combination RNA therapy e.g. anti-CCR5 ribozyme, TAR decoy, shRNA against Tat and Rev mRNA
Which modified viral proteins can we use to combat HIV?
RevM10 - mutant version of Rev that binds RRE in the viral RNA but unable export
Which modified cellular proteins can we use to combat HIV?
TRIM5a - 1 aa change to this cellular protein prevent HIV infecting the cell.
What are ZFNs used against?
CCR5 gene
