Lecture 19- Antivirals Flashcards
(13 cards)
Medical interventions against viral infection
Prevention of infection;
Vaccination
Treatment of viral disease
Mitigation of symptoms
Curative treatment= antiviral chemo
Antiviral chemotherapy
Treatment of viral infections using drugs which block viral infection/replication
Any step in replication can be theoretically targeted
Chemotherapy index;
Relative toxicity for host vs virus
Drugs MUST be toxic to the virus than the host- wider difference the better
Generic viral life cycle
All viruses follow same rough steps
Details can vary widely between viruses
- Delivery of genetic material
- Replication of genetic material
- Production of proteins
- Assembly of new virus
- Release of new virus
Effective targeting of antivirals
Type of virus= major implication for how the type of treatments possible
E.g. RNA vs DNA viruses
Mechanism of replication
Speed of evolution
Rational design of antivirals
Many antivirals = result of rational design
Structural info for targets
Computer aided drug design
Targeting viral replication - nucleoside analogues
Many viruses= use virally encoded enzymes to replicate viral nucleic acids preferentially
^different to human enzymes to provide a basis for specificity
Most nucleoside analogous = target RNA polymerases
Many broadly acting antivirals= nucleoside analogues
Acyclovir - acycloguanosine - broad acting antiviral
Active against a range of DNA viruses; HSV, varicella-zoster, Epstein-Barr, HCMV
Mimics guanosine in DNA replication
Results in premature chain termination when incorporated into DNA
Competitively inhibited DNA polymerase
Higher CMV action achieved by ganciclovir
Valaciclovir and valganciclovir = prodrugs
Ribavirin- broad acting antiviral
Acts against both RNA and DNA viruses
Guanosine analogue
Variety of proposed mechanisms;
- processed by inosine triphosphate pyrophosphate -> reduced activity = potentiates mutagenesis in HCV
- inhibits inosine monophosphate dehydrogenase = depletes cellular pools of GTP
- orientation of amide groups can make it look like adenosine / guanosine = leads to mutagenesis
10 fold inc in RNA virus mutagenesis = 99% loss in virus infectivity after a single round of infection
Targeting viral replication - non nucleoside analogues
Bind to allosteric sites on target proteins
Tend to be virus specific unlike nucleoside analogues
Widely employed in anti-HIV therapies
Target reverse transcriptase
Non-nucleoside reverse transcriptase inhibitors - Efavirenz
Common binding pocket for most NNRTIs
Prevents reverse transcription of viral ssRNA to dsDNA
First line highly active antiretroviral therapy drug
Drug analogues needed due to resistance!
HIV antivirals
Almost every step of the infection cycle can be targeted
Effective enough that most individuals can live a normal life
Significantly reduces HIV-related mortality and morbidity
Anti- influenza drugs
Serious respiratory illness in infants and elderly
Major causes of morbidity and mortality worldwide
High variability due to antigenic drift/shift complicates entry inhibitors
Requires a site of action conserved across all stains
Neuraminidase active site
Neuraminidase
Binding to sialic acid > engulfing virus > uncoating and virus replication
Zanamivir and oseltamivir
Developed through rational drug design based on x-ray structures
Zanamivir= requires negative charge for activity but this blocks oral uptake
Provided directly to respiratory tract via inhalation
Oseltamivir= administered as a prodrug - processed in liver
