Lecture 7 Flashcards
what is the first anti bacterial
-penicilin 1929
-inhibits bacterial cell wall synthesis
-broad spectrum G+ve, some G-ve
what was the first anti-viral
-iododeoxyuridine by william prussoff 1962
-inhibits viral nucleic acid synthesis
-works well against topical herpes virus
how many people were infected with hcv before?
170 million peeps
268 000 canadians
hcv was responsible for how much of chronic liver disease
40-60% leading cause of liver transplant
what is the % of hcv infected people get chronically infected
85%
true or false: there is no vaccine for hcv
true
what is chronic hcv aka how much time does it take to call it chronic
continuing hcv related disease without improvement for at least 6 months
how many % of hcv peeps show no symptoms
60-80%
slowly progressing lifelong disease
how many hcv peeps get cirrhosis and liver failure
10-20%
how many % of peeps get hepatocellular carcinoma due to hcv
3-5%
typically clinical symptoms appear during when for hcv peeps
during liver failure
-20y may elapse between infection and development of serious complications
who got the med nobel prize in 2020
-harvey alter, michael houghton and charles rice
-for discovery of hep c
true or false: chronic hcv is a curable disease
true
treatments of hcv from 1990 to 2001
-mostly inf started at like 5% response rate to 50% response rate
hcv treatment in 2011 and 2014
-inf+pi or NI
2011
-peg inf RBV
-75% response rate
2014
-peg inf rbv pi (DAA) or NI
-90% response rate
2015 hcv treatment
-inf free daas
-o2/o3 (DAA)
-close to 100% response rate
what does ns2 do in hcv
it autocleaves itself for other non structural viral replication
what are the 3 targets for hcv meds
-ns3 pro inhibitors
-ns5a inhibitors
-ns5b inhibitors
what is the ns3 protease
-trypsin like serine protease
-his, asp, ser at the catalytic triad
-pivotal role in polyprotein processing
-screening of small molecule compound library=no specific hits
what do high throuput molecule screenings do
screen for possible molecules that work against pathogens usually uses multi well plates with robots
what is the catalytic site for ns5a/b
ddivpc
n terminal product inhibition is observed for ns3/4a what is the sequence and the KI
ddivpc
-79um aka mid inhibition
what is cellular potency aka ec50
it is the minimum amount of the drug to kill 50% of the pathogen
what is ki
intrinsic potency
phase 1a-b DAA clinical study for the ns3 protease inhibitor
200 mg bid 2d, 2 log VL reduction aka now you need wayyyyyy less
why was the ns3 protease a lowkey fail
they had a bit cardio toxicity
what is faldaprevir
ns3/4a protease inhibitor
true or false: faldaprevir is a linear tripeptide with N-terminus carboxilic acid
false it is N terminus carboxylic acid that forms tight but non-covalent comprex with ns3 protease active sites
what are the doses effectiveness for faldaprevir
-once daily dose demonstrated up tp 83% svr in treatment naive phase 2 studies in combo with peginfa2a/rbv
what is major in vivo ns3 resistance
d168v(GY1b); rt155k (gt1a overlap with other PI)
faldaprevir is active against?
telapreveir and boceprevir mutant at v36, t54 or simeprevir q80 mutant
hcv polymerase function
-rna dependent rna polymerase
-catalyses the replication of hcv genomic rna
hcv pol amino acid homology with other viral pols
motifs a,b,c,d they are conservedt
when they screened hcv poly when they screened in a small molecule compound library they got multiple hit classes
true they even optimized it to have a bigger slay
called BI compound
phase 2-3 of deleobuvir
inf free all oral combination of bi207147+BI 201335 +rbv demonstrated svr 70-80%
what is BI207127
a potent reversible thumb site 1 non-nucleoside ns5b inhibitor
ns5b in vitro resistance:
aa changes at p495, p496 v499
-in vitro combination with BI 201335 suppresses emergence of resistant variants
true or false: the combination of ns3 and ns5 supresses emergence of resistant variants
yeah because all alone resistance develops fast
true or false: ns3 and ns5 phase 3 trial was a slay
nah BI yeeted out the project
why did BI phase 3 failed
they were brokeeeeeee
How was ns5a inhibitors discovered
by bms using a phenotypic screen using the replicon
ns5a inhibitors: no enzymatic function
-3 domain protein
-zinc binding protein
-homo dimeric protein
-membrane associated and formation of the replication complex
ns5a inhibitors: bristol myers squibb before and after optimization
-declatasvir
-ec50: 0.6nm
-ec50: 0.009 nm: gt1b
-0.050 nm: gt1a
hcv nucleoside inhibitor: mechanism pf action
you get the nucleoside
-the hcv ns5b pol incorporated the nucleotide that has the phospate group so signals end of chain
-you get terminated chain
Gilead and many other pharmaceutical companies
establish HCV nucleoside discovery programs;
– key attribute – pro-tide prodrugs deliver
monophosphate
– rapidly converts to active tri-phosphate inhibitor
In 2011 Gilead acquires Pharmasset for $11 billion
– had good nucleoside library
-access to HCV nucleoside analog, sofosbuvir
– SovaldiTM approved 2013 in combination with
IFN+RBV for Gt1 and Gt4
– Most HCV patients are cured after 12 weeks
main 2 drugs for hcv treatment
-Gilead’s Epclusa® for Gt1-6: 70% of market
made of: sofosbuvir (NS5B) and velpatasvir (NS5A)
-Abbvie’s MavyretTM for Gt1-6: 30% of market
made of: glecaprevir (NS3 PI) and pibrentasvir (NS5A)
Gilead first synthesized adenosine analogue GS5734 as an….
inhibitor for the HCV nucleoside
program; pro-tide optimized for oral administration,
entero-hepatic uptake and liver conversion to
triphosphate; inferior to sofosbuvir
adenosine analogue GS5734 active against
Paramyxoviridae, Coronaviridae and
Filoviridae
-not against ebola but was first to get approved for covidddd
initial hcv inf based treatments
– Low SVR rates (<50% in Gt1)
– Poor tolerance (high discontinuation rates)
– Required parenteral delivery
– Pegylated versions of IFN improve response (SoC)
Combinations of IFN/RBV with a direct acting antiviral improves response rates but…
– Cumulating side effects (IFN + RBV + DAA)
– Quick emergence of resistance to all single DAAs
– Variable SVR depending on genotype
IFN-free combinations of 2-3 DAAs finally lead to a cure for HCV infection in most patients
and for all genotypes:
N3 protease or NS5B polymerase inhibitors in combination with NS5A ligands lead to a
cure
