Lecture 7 Flashcards by Ezrah Isaac Roy

what is the first anti bacterial

-penicilin 1929
-inhibits bacterial cell wall synthesis
-broad spectrum G+ve, some G-ve

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what was the first anti-viral

-iododeoxyuridine by william prussoff 1962
-inhibits viral nucleic acid synthesis
-works well against topical herpes virus

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how many people were infected with hcv before?

170 million peeps
268 000 canadians

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hcv was responsible for how much of chronic liver disease

40-60% leading cause of liver transplant

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what is the % of hcv infected people get chronically infected

85%

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true or false: there is no vaccine for hcv

true

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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

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how many % of hcv peeps show no symptoms

60-80%
slowly progressing lifelong disease

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how many hcv peeps get cirrhosis and liver failure

10-20%

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how many % of peeps get hepatocellular carcinoma due to hcv

3-5%

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typically clinical symptoms appear during when for hcv peeps

during liver failure
-20y may elapse between infection and development of serious complications

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who got the med nobel prize in 2020

-harvey alter, michael houghton and charles rice
-for discovery of hep c

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true or false: chronic hcv is a curable disease

true

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treatments of hcv from 1990 to 2001

-mostly inf started at like 5% response rate to 50% response rate

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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

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2015 hcv treatment

-inf free daas
-o2/o3 (DAA)
-close to 100% response rate

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what does ns2 do in hcv

it autocleaves itself for other non structural viral replication

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what are the 3 targets for hcv meds

-ns3 pro inhibitors
-ns5a inhibitors
-ns5b inhibitors

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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

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what do high throuput molecule screenings do

screen for possible molecules that work against pathogens usually uses multi well plates with robots

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what is the catalytic site for ns5a/b

ddivpc

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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