antiviral (Dr. Cochrane) Flashcards
What is CC50?
Drug concentration at which reduces cell viability by 50%
How to find selectivity (SI) or therapeutic index (TI)?
CC50/IC50
What does a high TI/SI indicate?
drug is more selective to the virus targeted
what is drug clearance affected by?
i) metabolism in liver
ii) excretion through kidney/gut
Factors to consider when developing antivirals
i) toxicity of drug (try to minimize)
ii) efficacy of drug (better if done in low conc)
iii) drug delivery (how is the drug delivered to site of infection)
iv) drug clearance
v) how quick does drug resistance occur in virus?
Ways to deliver drug to targeted site
i) gut
ii) IV, inhalation, topical
iii) directly to site of infection (reduce toxicity while maximize drug efficacy)
What happens after pattern recognition receptors are activated?
signaling induced through IRF3/7 or NFkB
–> express interferons + proinflammatory cytokines
Pattern recongition receptors found on cell surface
TLR2,4,6
Pattern recongition receptors found on endosome
TLR3,7,8,9
Pattern recongition receptors found in cytoplasm
RIG-1, cGAS
What does TLR2,4 detect?
viral coat proteins
What does TLR7,8 detect?
ssRNA
What does TLR3, MDA5, RIG-1 detect
dsRNA
What does cGAS detect?
DNA
What does TRL9 detect?
hypomethylated CpG DNA
what PRR detects dsRNA?
TLR3, MDA5, RIG-1
what PRR detects DNA?
cGAS
what PRR detect viral coat proteins?
TLR2,4
What PRR detect hypomethylated CpG DNA?
TLR9
What PRR detect ssRNA?
TLR7,8
What happens after interferon interacts with its receptor?
signalling –> increase interferon-stimulated genes (ISG) expression
–> increase the cells’ ability to repsond and block virus replication
Types of interferon present
i) type I
ii) type II
iii)type III
examples of type 1 interferon
interferon alpha, beta
examples of type II interferon
interferon gamma
examples of type III interferon
interferon pheta
where are type I interferons found?
all nucleated cells
Where are type II interferons made?
T helper cells, NK cells, CD8 killer cells after they are activated
Examples where immune system leads to serious clinical outcomes
immune system hyperactivated (too much cytokines)
–> systemic inflammatory response syndrome (SIRS) or ARDS in Covid
–> multi-organ failure, systemic damage
Where is interferon treatment applied to?
hepatitus B, C with interferon alpha
–> more than 24 weeks
possible side effects of interferon treatment
have significant side effect reducing quality of life
Alternative approach to using interferon
activate innate immune system with TLR7/8 agonist (Imiquimod)
–> treat warts (HPV)
drugs that inhibit viral entry
i)Miraviroc
ii)T20
iii)Sunitinib (inhibits AAK1, GAK)
iv) lenacapavir (HIV-1, by binding to capsid)
How does Miraviroc work?
binds to CCR5 coreceptor –> compete with HIV-1 Gp120
How does T20 work?
mimic one of helical bundles
–> prevent six helical bundle from forming
Drugs that inhibit endosome release
i) chloroquine
ii) amantidine
How does chloroquine work?
prevent acidification of endosome needed for many virus
–> absorb protons to prevent pH change
How does amantidine work?
bind to M2 ion channel on influenza A virus
–> block ion flow
Why amantidine no longer recommmended for treatment?
lots of resistant virus formed
Drugs that inhibit viral genome replication
acyclovir
How does acyclovir work?
recognize and phosphorylate thymidine kinase of herpes virus
What viruses do acyclovir work on?
herpes virus
Herpes inhibitors present
i) Acyclovir (phosphorylate thymidine kinase)
ii) other chain terminators (e.g. famciclovir and other drugs with -vir)
iii)Foscarnet