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PDAT2 > 18 - Orjala Liver > Flashcards

18 - Orjala Liver Flashcards

1
Q

Viekira Pak

Combo for INF-Free HCV Treatment

A

ParitaPravir + OmbiAsvir + Ritonavir+Dasabuvir
NS3/4A Protease Inhibitor + NS5A + NS5B

All 3 types
but ritonavir –> HIV protease inhibitor –> inhibits CYP4503A4

  • *ONCE DAILY dosing of PARITAPREVIR**
  • *DASAbuvir BID**
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2
Q

Technivie
Partaprevir + Obitasvir

A

Viekira Pak WITHOUT Dasabuvir

GENOTYPE 4

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3
Q

Which Hepatitis?

Needs HBV to infect

Which Hepatitis?

Similar to A

A

HEP D = needs B

HEP E = Similar to HEP A

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4
Q

EPCLUSA

Sof + Vel

A

ALL GENOTYPES

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5
Q

Boceprevir // Telaprevir

HCV Treatments

A

Serine PROTEASE Inhibitors
HCV NS3/4A Serene protease
targets –> Translation & Polyprotein Processing

required for self-cleavege of polyprotein
during viral replication

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6
Q

Immune Modulators
INF

Chronic HBV Treatments

A

INTERFERONS = INF
host cytokines that modulate fxn of immune system

  • *Direct antiviral** via inhibition of viral replication
  • *Immunomodulatory** via enhancement of immunological response

for HBV / HCV
admin SQ or IM
TID dosing

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7
Q

Lamivudine

Cytidine Analogue

A

RT Inhibitor –> chronic HBV
HBV DNA polymerase has RT activity

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8
Q

DASAbuvir

A

NON-NUCLEOSIDE
​NS5B Polymerase Inhibitor​
binds to ALLOSTERIC SITE –> Genotype 1 selective
barrier to RESISTANCE to NON-Nucleoside inhibitors IS LOW

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9
Q

Uprifosbuvir

A

NS5B Polymerase Inhibitor

Uridine PRODRUG = similar MoA as SOF

still in development

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10
Q

Adefovir // Tenofovir

Adenosine Anologues

A
  • *RT Inhibitor –> chronic HBV**
  • originally for HIV*

Prodrugs –> oral BV
activated by adenylate Kinase

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11
Q

Entecavir

Guanosine nucleoside anologue

A

Inhibits THREE Distinct phases of HBV DNA Poly:
PRIMING
RT
Synthesis of the pos-stranded HBV DNA

originally for HERPES
converted intracellularly –> 5’ trisphosphate

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12
Q

Elbasvir

A

HCV NS5A Inhibitor

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13
Q

Which Hepatitis?

Small / Non-enveloped DNA virus
in the hepadnaviridae family

Blood / Infected Fluids
CHRONIC INFECTION –> Liver cancer risk

  • *Adult Acquired**
  • -> 95% virus clearence / persistance of surface antigen

Infant Acquired
>90% chronic infection

A

HBV

Hep B

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14
Q

HCV Treatments

A

PEG-INF + Ribavirin
used for BOTH HBV + HCV
approved for use WITH INF –> teratogenic
Combo approved for ALL HCV genotypes = SVR ~50%

Directly Acting Antiviral Agents

  • *NS5A Inhibitor = -A**svir
  • *NS5B (polymerase) Inhibitor = -B**uvir
  • *Protease Inhibitor** = -Previr’s
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15
Q

NS5B Polymerase Inhibitors

HCV Treatments

A

-buvirs

NS5B Poly is responsible for
Replicating the viral RNA genome
two approaches to find inhibitors:
ID of Nucleoside anologues –> fxn as ALT substrate inhibitors
&
Non-Nucleoside inhibitors that bind to allosteric sites on poly
–> nonfxnal enzyme

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16
Q

Harvoni

Combo for INF-Free HCV Treatment

A

SOF + Ledispavir
NS5B + NS5A

17
Q

HBV Treatments

A

VACCINE
is most effective

7 Drugs approved

  • *Immune Modulators** –> aid human immune system
  • *Anti-Virals** –> supress HBV by interfering with viral rep.

Often FAIL to completely elim HBV

18
Q

Ruzasvir

A

HCV NS5A Inhibitor

OPTIMIZED from ELBASVIR
ALL GENOTYPES

19
Q

Simeprevir

A
  • *MACROLIDE RING = FROZEN CONFIRMATION
  • -> high affinity!**

HCV PROTEASE Inhibitor
targets –> Translation & Polyprotein Processing
that came AFTER Boceprevir / Telaprevir

used in combo with Sofosbuvir

Developed using
SAR work = xray/modeling / medchem

20
Q

Telbivudine

Thymidine Nucleoside Anologue
B-L enantiomer of thymidine

A

Inhibits HBV DNA Polymerase –> chronic HBV

results in obligate chain termination of DNA synth

–> converted to 5’ triphosphate form intracellularly

21
Q

Which Hepatitis?

Positive-Sense / SS-RNA virus = Hepacivirus

NO VACCINE
goa is to get SVR (sustained virologic response)
–> 12 weeks after therapy

BLOOD transmission

~80% –> chronic infection

7 closely related genotypes
>50 subtypes

A
22
Q
  • *Immune Modulators**
  • *PEG-INFs**

Chronic HBV Treatments

A

Long-Acting PEGylated Interferon
covalent binding of ONE 40kda branched PEG polymer
–> Lysine side chain of IFN

IMPROVED:
PK / PKD’s –> longer half life / steady plasma conc

  • *ONCE PER WEEK VS TID
  • significant side effects***
23
Q

Sofosbuvir

Uridine Nucleotide Anlogue

enables INF-FREE regimens
PRICEY–> buthigh cure rate

A

HCV NS5B Polymerase inhibitor
alternative substrate inhibitor

Phosphoramidate PRODRUG –> enhanced potency
converted to Monophosphate by liver 1st pass
Active matabolite = TRI-phosphate made by kinases in LIVER

  • *CHIRAL**
  • *>10x** difference in activity between 2 isomers
  • *Active Diasteromer** obtained via selective crystalization
24
Q

Ombitasvir

A

HCV NS5A Inhibitor

Monotherapy –> low barrier of resistance

25
Q

Paritaprevir

A

Protease inhibitor
targets –> Translation & Polyprotein Processing
2014

26
Q

Velpatasvir

A

HCV NS5A Inhibitor
in combo w/ SOF

Genotypes 1-6

27
Q

HBV Structure

A

42nm Partially DS-DNA Virus

HBcAg = Nucleocapsid Core
surrounding by
HBsAg = Surface Antigen w/ lipoprotein coat

Genetic material:
dsDNA genome + DNA poly + Protein Kinase + Short RNA primer

28
Q

Which Hepatitis?

Vaccine Preventable
RNA in the picornavirus family

FECAL-ORAL transmission

NO CHRONIC infection

No Specific Medical Treatment

Immune Globulin

A

HAV

HEP A

29
Q

Ledispavir

A

NS5A Inhibitor
to beused in cobo with SOF

low barrier to RESISTANCE

30
Q

HBV Life Cycle

A

Cytokines / Antisense
Target Transcription / Protein Translation

Nucleoside analogs / Antisense
Target:
DNA Synthesis / RT / Primary Encapsidation

31
Q

Zapatier

Grazoprevir + elbasvir

A

Genotypes

1 + 4

32
Q

HCV STRUCTURE

A

~60nm Single-Stranded RNA virus
HCV RNA genome = 9.6kb in length
translated into a
Single Poly protein –> cleaved by Cellular + Viral Proteases

3 Structural Proteins = Core / E1 / E2

7 Non-Structural Proteins
p7 / NS2-3-4A-4B-5A-5B

33
Q

Grazoprevir

A

PROTEASE INHIBITOR
targets –> Translation & Polyprotein Processing
came after simeprevir

34
Q

NS5A Inhibitors

-Avir // -Pavir

A

HCV NS5A is critical for Viral Replication & ASSEMBLY
NS5A has no KNOWN enzymatic activity
mediated through interaction w/ other viral / cellproteins

Potent antivirals –> active in pM range
Symmetric DIMER or dimer-like
Two “peptidomimetic caps”witharomatic linker in the middle

PDAT2 (22 decks)

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