The Mechanism of Action of Anti-Viral Drugs Flashcards
what are viruses
obligate intracellular parasites
what are the current classifications
– Type and structure of the nucleic acid virion and the strategy used in its replication
– Symmetry of the capsid (icosahedral v helical)
– Presence or absence of a lipid membrane (envelope)
what’re the stages in a viral life cycle
- Attachment
- Penetration - by endocytosis
- Disassembly
- Transcription
- Translation
- Replication
- Assembly
- Release
what are the three broad group of treatments
– Virucides – directly inactivate viruses
– Antivirals – inhibit replication at the cellular level
– Immunomodulators
Targets for antiviral drugs
- Entry inhibition – virus binding to host cells
- Viral uncoating/disassembly e.g. amantadine/rimantadine
- Viral replication
- Viral polymerases e.g. HIV reverse transcriptase, HBV
- Viralproteasese.g.HIV,HCV
- Integrase
- Viral release inhibitors (neuraminidase)
Retroviruses
• Positive sense single stranded RNA virus
• Contains reverse transcriptase (RT) - an RNA-dependent DNA
polymerase, which makes a DNA copy of the viral RNA
• This DNA copy is integrated into the genome of the host cell
and it is then termed a provirus
• The provirus DNA is transcribed into both new genomic RNA and mRNA for translation into viral proteins using host cell machinery
• Some RNA retroviruses can transform normal cells into malignant cells
examples of retroviruses
HIV, human T cell leukaemia virus
the binding of HIV
Binds to CD4 and either CCR5 or CXCR4
what mediates HIV entry
Entry of HIV into a new cell is mediated by the Env glycoprotein spike (a trimer of gp120 and gp41)
Entry requires the receptor CD4 plus one of two co-receptors, CCR5 or CXCR4
HAART
- Combination therapy–classically 2NRTIs and additional drug from another class
- Prevention of morbidity and mortality associated with chronic HIV infection, at low cost of drug toxicity
- Reduction in sexual and vertical transmission of HIV
- Restore and preserve immunological function
RNA viruses
• RNA viruses are classified according to the sense (polarity) of their RNA
what are the two types of RNA virus
– Positive-sense viral RNA - similar to mRNA and can be immediately translated by the host cell
– Negative-sense viral RNA - complementary to mRNA and must be converted to positive-sense by an RNA dependent RNA polymerase before translation
what are the three types of RNA genome
dsRNA, +ssRNA, -ssRNA
where does virus replication occur
• Typically virus replication occurs in the host cell cytoplasm not
the nucleus
examples of RNA viruses
influenza, hepatitis C virus
Hepatitis C virus
• Flaviviridae family
– positive sense, single stranded RNA virus
– primarily transmitted through parenteral route, sexual transmission also recognised
– causes acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma
• Mainstay of therapy for many years was pegIFNα and ribavirin – now IFN-free combinations are first line
Influenza
• Orthomyxoviridae
– 3 distinct types: A, B and C
– enveloped, negative sense, single-stranded RNA virus
– Viral NA – catalyses removal of terminal sialic acids from glycoprotein. Allows mobility and elution of viral progeny
DNA viruses
- Entry of the viral DNA into the host cell nucleus
- Mostly use cellular enzymes for transcription and replication of their genomes
- Early and late mRNA transcripts are synthesized; early = regulatory proteins and proteins for DNA replication, late = structural proteins
examples of DNA viruses
herpes simplex virus, human papilloma virus, hepatitis B virus
Hepatitis B virus
• Hepadnavirus
– enveloped, partially dsDNA virus, genome maintained in circular confirmation
– causes acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma
– replication occurs via RNA intermediate (template for HBV polymerase)
Treatment of chronic HBV -• Immunomodulatory - pegylated IFNα
– Recombinant version of human IFN
– Variable response
– Finite treatment – 48 weeks
– AE = flu like illness, myalgia, depression, autoimmunity
