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antivirals Flashcards

1
Q

anitviral drugs

A
  • Most infectious disease in NA
    o 95% respiratory
  • All class 4 pathogens are viruses
    o Ebola, Marburg, lassa fever, hanta virus, small pox
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2
Q

class 1 pathogens

A

o No risk/limited risk
 Work on open lab bench (E.coli)
o P1 lab

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3
Q

class 2

A

o Moderate risk
o Limited access to lab
o Lab coat required
o Laminar hoods
 Herpes virus
o P2 lab

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4
Q

class 3

A

o Risk of death or serious illness
o Restricted access, special training required
o Surgical gowns, gloves, respirators
o All liquids/ air coming in/out is filtered
o Everything coming out is autoclaved and incinerated
 HIV , Y.Pestis, COVID
o P3 lab

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5
Q

class 4

A

o Lethal, highly infectious, untreatable
o Lab accessed by air lock, special training
o Space suit worn, shower going in and out
o Low pressure in lab (leaks will be IN), airlocks
o All liquids/gases are filtered/treated in and out
 Ebola, Marburg, Lassa fever, Hanta virus, smallpox
 P4 lab

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6
Q

viral structure

A
  • Genetic information
    o DNA/RNA
  • Surrounded by a capsid
    o Hollow container of protein
  • Some viruses may have
    o Enzymes
    o Regulatory proteins
  • Some viruses are enveloped
    o Capsid surrounded by a membrane
    o Remnant of the host cell membrane
    o Contains viral proteins
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7
Q

self-replicating

A
  • Viral proteins structurally related to host
    o Oncogenes
  • Viral proteins bind to host proteins and alter its function
    o Control cellular regulatory systems
  • Common elements
    o Duplication of genetic info
    o Production of viral protein
  • Viral process utilize host proteins and machinery
    o Ribosome
    o Nucleic acid polymerases
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8
Q

difficulties in developing antiviral drugs

A

o Difficult to target with drugs
o Proteins bind to each other very tightly
o Utilize large contact surfaces
o Need to avoid interfering with normal host cells

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9
Q

cell signaling systems use protein binding

A

whereby protein a attaches to protein b via the active site and conformational change to transmit a signal into the cell
viruses do the same thing (replace protein A with a virus and protein b will change into another shape to fit the virus) a viral message will be sent into the cell instead

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10
Q

blocking viral binding

A

attach a big molecule on protein B to block viral enzyme from binding and transmitting a signal. difficult to do b/c its a large surface area and big drugs are bad drugs because of bioavailability

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11
Q

viral enzymes as drug targets are difficult b/c

A

o Host cells make nucleic acids
o Substrates, mechanisms, and structures are similar
o How do you block viral enzyme without blocking host enzyme?
 Limited number of targets
* Most viruses have small genomes (4 genes)
* 1-2 enzymes
o Most involve nucleic acids (host selectivity problem b/c we have similar)
o Only few antiviral drugs exist hepatitis C (cure), herpes (treat) and HIV (manage)

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12
Q

problems w/antiviral drugs

A
  • Selectivity
    o Kill virus w/o killing host
  • Diagnosis
    o Drugs specific for each virus
    o Many viruses have similar symptoms
    o Need biochemical test
  • Resistance
    o Mutation rates in viruses is high
    o Viruses quickly develop resistance to drugs (days or weeks)
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13
Q
  1. Absorption and penetration into cell
A

o Virus binds to host on outside of host membrane
 Capsid binds directly and is passed inside before opening
 Envelope of capsid fuses with host cell membrane releasing capsid inside cell
o Genetic info of virus injected into host
 Can inject viral protein
o This stage is poor drug targets b/c
 Binding is protein-protein binding
* SA very large
* Difficult to inhibit protein-protein binding with small molecules
 Limited success in HIV
* Fuzeon (peptide with 36 AA)
* Maraviroc (small molecule + fits into HIV protein)

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14
Q
  1. Capsid opens releasing contents
A

o Capsid releases genetic info into cell
o Difficult to target bc protein-protein interactions, pH changes)
o 2 successful drugs
 Influenza
* Block ion channel

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15
Q
  1. Synthesis of regulatory proteins
A

o Viral proteins made + take over normal cell systems
o Nucleic acid replication
o Expression of viral protein
o Suppression of host cell defenses
o Binding to host proteins
o No drug for this

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16
Q
  1. Synthesis of RNA or DNA
A

o Viral genome replicated using host enzymes
o Some viruses have their own enzymes for this (drug targets)
o Most anti-viral drugs target this phase
 Require unique viral enzyme
 Prevent viral nuclei acid synthesis

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17
Q
  1. Synthesis of structural proteins
A

o Utilize host ribosome
 Poor drug target
o Some viruses utilize specific enzymes for protein maturation
 Protease drugs
* HIV
* Hepatitis C

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18
Q
  1. Assembly of viral particles
A

o Capsid proteins self-assemble
 Nuclei acid inside
 Viral proteins outside
o Release may destroy cell
 Lytic virus (herpes/influenza)
o Cell may remain intact
 Papilloma, herpes
o Few drug targets (HIV, influenza)
* Release from host

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19
Q

antiviral drugs require viral enzyme targets

A
  • Enzyme should structurally be unrelated to host enzymes (selectivity)
  • Most viral enzymes are involved in nucleic acid replication
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20
Q

herpes

A
  • Causes chronic recurrent infections
  • Able to escape immune system (hides in nerve cell)
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21
Q

herpes structure

A

o Genetic info is double stranded DNA
 >70 genes
 Has its own polymerases- drug target
o Components of nucleic acid
 Nucleoside (no phosphate)
 Sugar (DN/RNA)
 Base (ATCG) heterocycle (ring with heteroatoms)
* Recognized by shape and hydrogen not letter
* Draw nucleic acid
o Polymerases copy nucleic acids
 Use one strand as template to make another strand
* Nucleotides are added one at a time, matching bases

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22
Q

rational drug design herpes

A

 Use knowledge of enzyme mechanism and substrate to design drug
 Selectivity issue w/nucleic acids
* Must block viral enzyme w/o blocking host enzyme

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23
Q

poor selectivity= toxicity herpes

A

interference with normal cell f’n causes problems

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24
Q

strategy 1 herpes add non natural base

A

add non natural base on DNA strand instead of normal ATCG
Causes disruption of nucleic acid and causes spelling error that DNA wont be read by other enzymes
requires:
 Drug is a substrate for a kinase (to be phosphorylated))
* Host
* Virus (rare)
 Drug is a substrate for viral polymerase
* Incorporated into viral nucleic acid
* Create an unreadable strand
* Drug must not be a substrate for host polymerase (side effects)

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25
Q

strategy 2 herpes chain terminator

A

add isostere on 3’ OH as a biological replacement
o Requirements for chain termination
 Drug is phosphorylated (host or virus)
 Drug substrate for viral polymerase
* Incorporated into viral nucleic acid
* Stops replication
* Viral proteins don’t get made
 Drug must not be a substrate for host polymerase

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26
Q

Idoxuridine

A
  • Substrate for viral and host polymerase
  • Highly toxic
  • Topical use
    o Limits exposure to body
    o Eye infections of herpes
  • Proof of principle—antiviral drug is possible but ideally not good
27
Q

o Chain termination—selectivity is a problem

A

 Drugs have structures too similar to normal substrate
* These drugs incorporated into host nucleic acid by host polymerase
* Many terminators are toxic
 Improve selectivity by changing sugar from 3’ to 2’ or opening sugar
the host polymerase will not accept open sugar but viral will

28
Q

open sugar chain terminator Acyclovir (CT)

A
  • Very selective for virally infected cells
  • Low incidence of side effects
  • Low severity side effects
  • Selectivity due to selective bioavailability
  • Accepted by viral polymerase not host
  • Topical cream in NA does not work but works in Europe
  • Is a prodrug add PO3 on OH end
    traps acyclovir in infected cells and is concentrated
    draw phosphorylation
29
Q
  • HSV-1
A

o Cold sores and blisters on mouth nose, eye
 80% infected
 10-20% experience outbreaks
o Virus escapes eradication by hiding in neurons
 Activate by no access to immune system, stress, sunlight, epithelial cells
o Lytic infection
 Only in epithelial cells, no damage neurons
 Viral activity 24hrs
 Minimal damage
 Damage caused by immune system
* Overstimulated and destroys tissue
* Drug administered quickly

30
Q
  • HSV-2
A

o Blisters on anus and genitals
o 15%-20% infected
o More virulent and painful
o One outbreak per year
o Most damage done by immune system, administer drug quickly

31
Q

influenza structure

A

o Enveloped virus
 Human membrane that virus steals when it leaves
o Enveloped embedded w/2 viral proteins
o Neuraminidase (viral maturation)
o Hemagglutinin (viral entry)
 Antibody test to identify them as they are on the outside of virus

32
Q

influenza life cycle

A

o Virus life cycle start with binding
 Virus hemagglutinin binds to host glycoproteins containing sialic acidsugar
o Endosome forms
o Virus envelope and cell membrane fuse
o Contents spill into cell
o Viral RNA and proteins are replicated
* Capsid self-assemble with RNA
* Capsid form inside cell complete RNA
* Viral envelope proteins accumulate on cell membrane
o Hemagglutinin
o Neuraaminidase
* Virus particles bud from the cell
* Virus particles still contain host proteins
o Host proteins may contain sialic acid (sugar)
 If sialic acid remains on the virus, hemagglutinin form other virus particles will stick
o This will cause virus particles to clump together
 To prevent this, neuraminidase removes sialic acid from host proteins on the virus envelop
 Virus particles don’t stick together
o Immature virus stick to each other

o Neuraminidase removed the sialic acids

DRAW

33
Q

Neuraminidase

A
  • Essential enzyme
    o Highly conserved—other viral proteins variable
  • Cuts bond between sialic acid and other sugars in virus
    o Mechanism of hydrolysis
    o Enzymes bind to transition state (rational drug design= mechanism, enzyme for trans, design drug that binds trans to enzyme similar to the trans)
    o Trans state vs trans state mimic
34
Q

Xray crystallography

A
  • Crystallize molecule
  • Bombard crystal with x ray beam
    o Wavelength similar to bond lengths
  • Xray are scattered by interaction with atoms in crystals
    o Angle determined by WL and bond distance
    o Bragg equation
  • Crystal generates large scale order
    o All molecules arranged in a fixed lattice
    o Magnifies the affect ( all molecules diffract the same way) = diffraction pattern
  • Computer calculates the e density map
    o Molecular formula known
    o Fix molecular structure into the EDM
    o Technique important for accelerator design
     Designed to incorporate beam lines
35
Q

tamiflu

A
  • Very expensive
  • Limited supply
  • Given in first 24-48hrs
  • Diagnosis problem (flu vs cold; symptoms are the same)
    o Only works for influenza (20% colds)
  • Reduces disease by 1 day
  • Benefit/risk analysis indicates clinical use is questionable
  • Toxicity issues
  • Patent expired in 2017
    o Generic companies cannot replicate b/c they cant replicate raw material (why cant they?)
36
Q

hepatitis characteristics

A

o Single stranded RNA
o Small genome
o Protein is cut into smaller proteins
 First few released by host proteases
 Remaining is cut by viral proteases
o Virus has an RNA dependant RNA polymerase
 Copies viral RNA
o Virus proteins spontaneously assemble around viral RNA
o Transported in blood to liver as a complex with lipopolysaccharides
o Virus is replicated inside membrane of ER
o Viral enzymes
 RNA dependant RNA polymerase (makes viral RNA copies)
 Protease (cuts viral polypeptide into small proteins)

37
Q

viral enzymes HC

A

 RNA dependant RNA polymerase (makes viral RNA copies)
 Protease (cuts viral polypeptide into small proteins)

38
Q

inhibiton of viral polymerase HC

A

 Sofobuvir
* Prodrug
* Active drug is a chain terminator

39
Q

inhibiton of viral enzyme formation HC

A

 Large protein binds to a small protein to form functional enzyme
 Ledipasvir
* Sticks to small protein
* Prevents protein association and formation of viral enzyme
* Doesn’t follow Lipinski
 Harvoni
* Combination of ledipasvir and sofobuvir
* Capable of curing HCV infection 8-24 weeks

40
Q

AIDS

A
  • Patients suffered from T-cell depletion
    o Key components of immune system
  • Victims dies from opportunistic infections
    o Normally ctl by a healthy immune system
41
Q

HIV

A

o Agent causes AIDS
o Spread
 Unsafe sexual practice
 Intravenous drug use
 Congenital infection of newborns
 Fluid transfers
o Targets CD4 cells of immune system
o Virus may have spread from chimpanzees

42
Q

Retrovirus HIV

A

 Viral genome is carried by single stranded RNA
 Viral enzyme—reverse transcriptase: copies ssRNA into dsDNA (what infects the person)
 RT destroys RNA template as it is copied
* RT uses the single stranded DNA to prepare double stranded viral DNA

43
Q

Replication HIV

A

 Virus binds CD4 protein on outside of cells
 Virus envelope fuses w/membrane and injects capsid inside
 Capsid opens, RT copies viral RNA into dsDNA
 Viral integrase enzyme inserts viral DNA into host chromosome—infection permanent
 Viral genome activatesviral RNA is made, single viral protein is made
 Viral protease cuts itself out of viral protein and cuts the viral protein into smaller viral proteins
 Virus particles self-assemble around viral RNA
 Virus buds from the cell taking membrane piece with it (envelope)

44
Q

HIV Drug targets

A

RT (Chain terminator), protease, GP41 (Changes shape)
not good–intergrase, RNAase H, GP120

45
Q

Acute phase HIV (6-10 WKS)

A

o Flu like symptoms
o High viral titters
o Phase ends when immune system reduce viral load (get infection under ctrl)

46
Q

Chronic Phase (8-12)

A

o Asymptomatic
 Fully infectious
 Viral replication is high 10^9)
 Immune system destroys viral particles
 Few viruses escape to continue infection
 CD4 cells in IS slowly depleted
* Helps; no symptoms b/c IS taking care, but leakage causes virus to remain
 Phase ends when IS runs out of CD4 cells

47
Q

AIDS phase (2-4)

A

o Secondary infections
o Person fully infectious
o Viral replication is very high
o High viral titers
o Immune system is completely destroyed
o Secondary infectious cannot be cleared by immune system
o Person dies b/c of secondary infection

48
Q

AZT

A
  • Failed ad a cancer drug
  • Toxic
  • Tested against HIV
  • Gained FDA approval after truncated clinical trial
    o Terminated b/c of ethical grounds
49
Q

AZT failed b/c

A

o Short period of antiviral activity
o Resistant virus appears in few weeks and drug no longer works
 RT is error prone
* Enzyme has 2 domains (functions
o Polymerase
o RNASE H
o Enzyme destroys template RNA as it copied (RNAse H)
 As RT makes DNA,
* No error checking
o Virus in the body is different b/c of mistake
* Sloppy replication
 Very high mutation rate
* 1 althernation/genome
* Every virus particle is different

50
Q

3TC racemate ACT

A
  • Natural enantiomer highly toxic
    o Substrate host polymerase
  • Unnatural enantiomer low toxicity
    o Not recognized by host enzymes
  • Pseudoenantiomers have diff toxicities
    o Natural highly toxic
     Substrate for host kinase and polymerase
    o Unnatural low toxicity
     Substrate for host kinase
     Nucleotide not recognized by host polymerase
51
Q

Patent for 3TC

A
  • Drug is unnatural enantiomer by Bernard Belleau
  • Patent
    o Described as racemate
    o Isomers can be separated but did not say how
    o Patent pure enantiomers and did not say how to make them
    o Clinical trials
     Drug low toxicity
     Resistance appeared quickly in drug
     Effective if combined with AZT
     Approved
     1 billion/yr 2000
52
Q

Liotta

A

 Noticed patent did not describe how to make enantiomers of 3TC
 Discovered a method to make pure enantiomers
 Patent both synthesis
 Holds right to the company’s drug
 Negotiated licence agreement with OG’S
 Also noticed company missed key compound
* Fluorinated analogue was common change when non-natural base anticancer drugs were developed
* Patented FTC

53
Q

HIV protease

A

Essential enzyme
Cleavage of long viral peptide into smaller viral proteins
Aspartyl protease
Active site has 2 conserved aspartic acids
know mechanism!!!!!!!!!!!!!!!!!!!!!!!!!!!

54
Q

Approved Protease Inhibitors

A

hard to manufacture on large scale because of complexity i.e chiral centers, large molecules, poor bioavailbility (rule of 5), high dose required, impossible manufact economically

55
Q

cost of drugs is small

A

Most of the cost of drugs is not the active ingredient
Marketing
Research
Infrastructure
Until AIDS, no drug program had ever been cancelled because the drug itself was too hard to manufacture

56
Q

indinavir

A

Utilized brand-new catalytic methods to construct stereocentres

57
Q

HIV resistance

A

HIV replicates rapidly
10 billion new viral particles every day
Replication sloppy–RT no error checking, each virus particle is diff so resistance is fast n drug cant keep up
The genome of each virus is different
Resistant mutants generated every day
Anti-HIV agents select resistant strains unless all viral proliferation is blocked
No single anti-HIV agent is powerful enough to do this

58
Q

Combination Therapy

A

If one drug fails, second picks up slack
Third drug provides insurance
Virus resistance more difficult

59
Q

HAART

A

Highly Active Antiretroviral Therapy
Combination of 3 drugs
Compliance
16 or more HIV pills a day
Complex regimen
with/without food, empty stomach, without other drugs etc…
side effects: rash, nightmares, lipodistrophy (forever lose fat in cheeks)
Compliance problems produce resistance b/c they would stop taking it at the specific time

60
Q

Patient compliance problem

A

HAART therapy initially very successful
Improved quality of life
Side effects severe, dosing inconvenient
Appearance of resistance and increased spread
Patients skipped doses
Regression to high risk behaviours
Second generation drugs designed to be more “drug like”
Reduced side effects
Convenient dosing

61
Q

Patient compliance solution

A

Current therapies based on “clean” drugs
Pseudoenantiomer Nucleosides
3TC, FTC
Few side effects
Good patient compliance

62
Q

HIV is a manageable infection in developed world

A

Lifespan now more than 20 years
Disease cannot be cured
Mild side effects
Can manage the progression of the illness

63
Q

Current Therapies HIV

A

Pseudoenantiomer nucleosides
3TC
FTC (Liotta)
Clean drugs
Integrase inhibitors
Second generation Protease inhibitors
Improved properties

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