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Business of science > Lecture 7 > Flashcards

Lecture 7 Flashcards

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Biology 101 flashcards
1
Q

what is the first anti bacterial

A

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

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2
Q

what was the first anti-viral

A

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

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3
Q

how many people were infected with hcv before?

A

170 million peeps
268 000 canadians

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4
Q

hcv was responsible for how much of chronic liver disease

A

40-60% leading cause of liver transplant

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5
Q

what is the % of hcv infected people get chronically infected

A

85%

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6
Q

true or false: there is no vaccine for hcv

A

true

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7
Q

what is chronic hcv aka how much time does it take to call it chronic

A

continuing hcv related disease without improvement for at least 6 months

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8
Q

how many % of hcv peeps show no symptoms

A

60-80%
slowly progressing lifelong disease

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9
Q

how many hcv peeps get cirrhosis and liver failure

A

10-20%

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10
Q

how many % of peeps get hepatocellular carcinoma due to hcv

A

3-5%

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11
Q

typically clinical symptoms appear during when for hcv peeps

A

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

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12
Q

who got the med nobel prize in 2020

A

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

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13
Q

true or false: chronic hcv is a curable disease

A

true

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14
Q

treatments of hcv from 1990 to 2001

A

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

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15
Q

hcv treatment in 2011 and 2014

A

-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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16
Q

2015 hcv treatment

A

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

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17
Q

what does ns2 do in hcv

A

it autocleaves itself for other non structural viral replication

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18
Q

what are the 3 targets for hcv meds

A

-ns3 pro inhibitors
-ns5a inhibitors
-ns5b inhibitors

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19
Q

what is the ns3 protease

A

-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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20
Q

what do high throuput molecule screenings do

A

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

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21
Q

what is the catalytic site for ns5a/b

A

ddivpc

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22
Q

n terminal product inhibition is observed for ns3/4a what is the sequence and the KI

A

ddivpc
-79um aka mid inhibition

23
Q

what is cellular potency aka ec50

A

it is the minimum amount of the drug to kill 50% of the pathogen

24
Q

what is ki

A

intrinsic potency

25
Q

phase 1a-b DAA clinical study for the ns3 protease inhibitor

A

200 mg bid 2d, 2 log VL reduction aka now you need wayyyyyy less

26
Q

why was the ns3 protease a lowkey fail

A

they had a bit cardio toxicity

27
Q

what is faldaprevir

A

ns3/4a protease inhibitor

28
Q

true or false: faldaprevir is a linear tripeptide with N-terminus carboxilic acid

A

false it is N terminus carboxylic acid that forms tight but non-covalent comprex with ns3 protease active sites

29
Q

what are the doses effectiveness for faldaprevir

A

-once daily dose demonstrated up tp 83% svr in treatment naive phase 2 studies in combo with peginfa2a/rbv

30
Q

what is major in vivo ns3 resistance

A

d168v(GY1b); rt155k (gt1a overlap with other PI)

31
Q

faldaprevir is active against?

A

telapreveir and boceprevir mutant at v36, t54 or simeprevir q80 mutant

32
Q

hcv polymerase function

A

-rna dependent rna polymerase
-catalyses the replication of hcv genomic rna

33
Q

hcv pol amino acid homology with other viral pols

A

motifs a,b,c,d they are conservedt

34
Q

when they screened hcv poly when they screened in a small molecule compound library they got multiple hit classes

A

true they even optimized it to have a bigger slay
called BI compound

35
Q

phase 2-3 of deleobuvir

A

inf free all oral combination of bi207147+BI 201335 +rbv demonstrated svr 70-80%

35
Q

what is BI207127

A

a potent reversible thumb site 1 non-nucleoside ns5b inhibitor

35
Q

ns5b in vitro resistance:

A

aa changes at p495, p496 v499
-in vitro combination with BI 201335 suppresses emergence of resistant variants

36
Q

true or false: the combination of ns3 and ns5 supresses emergence of resistant variants

A

yeah because all alone resistance develops fast

37
Q

true or false: ns3 and ns5 phase 3 trial was a slay

A

nah BI yeeted out the project

38
Q

why did BI phase 3 failed

A

they were brokeeeeeee

39
Q

How was ns5a inhibitors discovered

A

by bms using a phenotypic screen using the replicon

40
Q

ns5a inhibitors: no enzymatic function

A

-3 domain protein
-zinc binding protein
-homo dimeric protein
-membrane associated and formation of the replication complex

41
Q

ns5a inhibitors: bristol myers squibb before and after optimization

A

-declatasvir
-ec50: 0.6nm
-ec50: 0.009 nm: gt1b
-0.050 nm: gt1a

42
Q

hcv nucleoside inhibitor: mechanism pf action

A

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

43
Q

Gilead and many other pharmaceutical companies
establish HCV nucleoside discovery programs;

A

– key attribute – pro-tide prodrugs deliver
monophosphate
– rapidly converts to active tri-phosphate inhibitor

44
Q

In 2011 Gilead acquires Pharmasset for $11 billion

A

– 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

45
Q

main 2 drugs for hcv treatment

A

-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)

46
Q

Gilead first synthesized adenosine analogue GS5734 as an….

A

inhibitor for the HCV nucleoside
program; pro-tide optimized for oral administration,
entero-hepatic uptake and liver conversion to
triphosphate; inferior to sofosbuvir

47
Q

adenosine analogue GS5734 active against

A

Paramyxoviridae, Coronaviridae and
Filoviridae
-not against ebola but was first to get approved for covidddd

48
Q

initial hcv inf based treatments

A

– Low SVR rates (<50% in Gt1)
– Poor tolerance (high discontinuation rates)
– Required parenteral delivery
– Pegylated versions of IFN improve response (SoC)

49
Q

Combinations of IFN/RBV with a direct acting antiviral improves response rates but…

A

– Cumulating side effects (IFN + RBV + DAA)
– Quick emergence of resistance to all single DAAs
– Variable SVR depending on genotype

50
Q

IFN-free combinations of 2-3 DAAs finally lead to a cure for HCV infection in most patients
and for all genotypes:

A

N3 protease or NS5B polymerase inhibitors in combination with NS5A ligands lead to a
cure

51
Q
A

Business of science (21 decks)

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