Antiviral Therapies Flashcards
Microcephaly
Zika virus
Definition of a virus
Obligate intracellular parasites
What is the composition of a virus
Genome comprised of DNA nad RNA
Viral genome is replicated and directs th synthesis
Examples of symmertrical protein capsid
Adenovirus
Picornavirus
Calicivirus
Non-enveloped
Examples of eneveloped virus
Lipid envelope derived from host membrane
Pleimorphic: measles virus (variation in size)
Ebola virus
Examples of combination of capsid and envelope
Herpes virus
How is a virus named
The disease: polio
Person who discovered it: epstein barr
Place it was discovered: coxsackievirus
Part of the body affected: rhinovirus, hepatitis
Way it is spread: dengue, influenza
What is the negative sense
Complimentary strand of the messenger RNA
What are the consequences of viral genome type
RNA viruses and retroviruses use own polymerase to replicated - lack proof reading capacity high mutation rate
RNA less stable - size is limited
RNA viruses use complex codign stragies to make more proteins
DNA are big - accessory genes are not essential but can modify the host immune response, often lost in passage in culture
Segmented genomes - allows additional easy form of recombination, but imposes more difficult packaging stategies
How many influenza virus are made for every 1 entering the cell
1000 are made
What is the cytopathic effect
Death of the cell caused by virus
Lysing of the cell
Shut down of host protein synthesis or accumulation of viral proteins
Viruses form plaques
As the virus has replicated, it kills cells and leaves a hole which is stained clear
How is plaque assay useful
Can see how many viruses present
What si syncytia assay
Viruses with surface portein that fuse cells together
HIV
Viral diagnosis
Genome: PCR, RT-PCR
Antigen: IFA, ELISA - use antibodies to stain cells
Virus particles: electron microscopy
Cytopathic effect - virus isolaiton
Antibodies against virus - serology
How do we manipulate viruses
So small they can be synthesised
Introduce synthetic DNA or RNA - driven to replicate
Allows reverse genetics - engineer vaccinations
Why is it hard to treat viruses
Infect host cells - cannot target those
Have to find things that viruses do that host cell doesn’t
What do most of the antiviral drugs do
Target viral enzymes - by rational drug design
Nucleoside analogues - inhibit with nucleic acid replication - however need to element of specificity
What is acyclovir
Nucleoside analogue
Looks like guanosine
Whole bottom half is missing so 3’ - OH cannot attach in nuecleotide chain, prevention of phosphodiester bond
Chain terminator
Why is acyclovir so good for specificity
Exist in its unphophorylated form
Aciclovir can only be phosphorylated by viral thymidine kinase only encoded in herpes virus
Rest of the steps are using cellular enzymes
aciclovir tirphosphate has higher affinity for viral DNA polymerase than host cell
What is remdesivir
nucleoside analogue
analogue of adenose - chain termination 3 nucleotides downstream
it twists the shape of the molecule so no more nucleotides can be added
used for ebola but more recently used for COVID
What is important for an antiviral drug
Target a unique and essential gene
Be effective against a range of influenza types
Be easy to administer even to very sick patients
Few side effects
How does adamantanes/rimantadine work
Cyclic amines with bulky cagelike structures
Byproducts of petroleum refinement
Active against influenza A molecule
TARGET: Sit in the middle of a tetrameric ion channel specifically coded by influenza virus known as M2 ion channel
M2 allows H+ from acidic enviornment of endosome to virus core
Undo interactions holdign virus together
Release of genome by uncoating of virus
Resistance to adamantadine
Single point mutation on M2 for amantadine to no longer bind (S31N)
Little cost to fitness
Most H3N2 are resistant
H5N1 bird flu
Swine flue pH1N1
What type of structure is neuraminidase
Tetrimeric
Why is neuraminidase important in the replication cycle
Virion budds out
If no NA hemagglutinin will stick back down to the sialic acid
Neuraminidase enzyme that cleaves sialic acid
Enable virus to be released
How long do NAI shorten illness
17 hrs to 29hrs
Retrospective analysis of tamiflu use in 2009 pandemic
Halved risk of death if started within 48 hours of symptoms
What are examples of neuraminidase inhibitors
Relenza
Tamiflu
What are the resistance to osetamivir
Histatine to tyrosine 274
H1N1 - 2007/08
Are all 4 NAI circulating today susceptable to NAI
yes
What is baloxavir
Viral polymerase of influenza structure has been solved
Baloxavir inhibits PA endonulcease enzyme
Baloxavir resistants
Single point mutation PA I38T
Mutation observed in H3N2 after treatment in children
Facts about hepatitis C virus
Foudn its way in blood products
170 million people are are infects
4% will have carcinoma
Why aren’t people with HIV cured
HIV retrovirus
Integrates itself into the DNA
Reservior cells
Who are the people who are cured of HIV
Blood marrow transplant
Using people who are resistant to HIV - mutation in CCR5 gene at delta 52
Makes CCR5 not expressed
HIV cannot enter new cells
What are biological virus treatment
Passive immunotherapy - anitbodies from recovered individuals
What is plaivizumab
Humanized monoclonal anitbody against F fusion protein
Against RSV
55% reduced hospitalisation
What viral drugs don’t work for COVDI
Ribavirin
Chloroquine
Lopinavir
Ritonavir
What other treatments are there for COVID
M protease inhibitors
Remdesivir
Favipiravir
Toculizimab - IL6 antibody
Dexamethasone - steroid
What is the difference in patients who are given remdesivir
The more oxygen and mechanical ventilation - the more ineffective the treatment
What is the difference in dexamethasone for treatment of SARS
Dexamethasone more effective in mechanical ventilation
What is the future for antiviral therapy
New antiviral therapies that target the host
Broad acting antivirals
Combinations of drugs
Delivery systems suitable for target population
D
Why is relenza not as good as a drug as tamiflu
Chemistry of relenza means that virus more readily acquires resistance
