18 - Orjala Liver Flashcards
Viekira Pak
Combo for INF-Free HCV Treatment
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**
Technivie
Partaprevir + Obitasvir
Viekira Pak WITHOUT Dasabuvir
GENOTYPE 4
Which Hepatitis?
Needs HBV to infect
Which Hepatitis?
Similar to A
HEP D = needs B
HEP E = Similar to HEP A
EPCLUSA
Sof + Vel
ALL GENOTYPES
Boceprevir // Telaprevir
HCV Treatments
Serine PROTEASE Inhibitors
HCV NS3/4A Serene protease
targets –> Translation & Polyprotein Processing
required for self-cleavege of polyprotein
during viral replication
Immune Modulators
INF
Chronic HBV Treatments
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
Lamivudine
Cytidine Analogue
RT Inhibitor –> chronic HBV
HBV DNA polymerase has RT activity
DASAbuvir
NON-NUCLEOSIDE
NS5B Polymerase Inhibitor
binds to ALLOSTERIC SITE –> Genotype 1 selective
barrier to RESISTANCE to NON-Nucleoside inhibitors IS LOW
Uprifosbuvir
NS5B Polymerase Inhibitor
Uridine PRODRUG = similar MoA as SOF
still in development
Adefovir // Tenofovir
Adenosine Anologues
- *RT Inhibitor –> chronic HBV**
- originally for HIV*
Prodrugs –> oral BV
activated by adenylate Kinase
Entecavir
Guanosine nucleoside anologue
Inhibits THREE Distinct phases of HBV DNA Poly:
PRIMING
RT
Synthesis of the pos-stranded HBV DNA
originally for HERPES
converted intracellularly –> 5’ trisphosphate
Elbasvir
HCV NS5A Inhibitor
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
HBV
Hep B
HCV Treatments
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
NS5B Polymerase Inhibitors
HCV Treatments
-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
Harvoni
Combo for INF-Free HCV Treatment
SOF + Ledispavir
NS5B + NS5A
HBV Treatments
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
Ruzasvir
HCV NS5A Inhibitor
OPTIMIZED from ELBASVIR
ALL GENOTYPES
Simeprevir
- *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
Telbivudine
Thymidine Nucleoside Anologue
B-L enantiomer of thymidine
Inhibits HBV DNA Polymerase –> chronic HBV
results in obligate chain termination of DNA synth
–> converted to 5’ triphosphate form intracellularly
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
- *Immune Modulators**
- *PEG-INFs**
Chronic HBV Treatments
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***
Sofosbuvir
Uridine Nucleotide Anlogue
enables INF-FREE regimens
PRICEY–> buthigh cure rate
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
Ombitasvir
HCV NS5A Inhibitor
Monotherapy –> low barrier of resistance
Paritaprevir
Protease inhibitor
targets –> Translation & Polyprotein Processing
2014
Velpatasvir
HCV NS5A Inhibitor
in combo w/ SOF
Genotypes 1-6
HBV Structure
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
Which Hepatitis?
Vaccine Preventable
RNA in the picornavirus family
FECAL-ORAL transmission
NO CHRONIC infection
No Specific Medical Treatment
Immune Globulin
HAV
HEP A
Ledispavir
NS5A Inhibitor
to beused in cobo with SOF
low barrier to RESISTANCE
HBV Life Cycle
Cytokines / Antisense
Target Transcription / Protein Translation
Nucleoside analogs / Antisense
Target:
DNA Synthesis / RT / Primary Encapsidation
Zapatier
Grazoprevir + elbasvir
Genotypes
1 + 4
HCV STRUCTURE
~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
Grazoprevir
PROTEASE INHIBITOR
targets –> Translation & Polyprotein Processing
came after simeprevir
NS5A Inhibitors
-Avir // -Pavir
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
