18 - Orjala Liver Flashcards by Karlo Sison

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**

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Technivie
Partaprevir + Obitasvir

Viekira Pak WITHOUT Dasabuvir

GENOTYPE 4

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Which Hepatitis?

Needs HBV to infect

Which Hepatitis?

Similar to A

HEP D = needs B

HEP E = Similar to HEP A

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EPCLUSA

Sof + Vel

ALL GENOTYPES

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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

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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

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Lamivudine

Cytidine Analogue

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

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DASAbuvir

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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Uprifosbuvir

NS5B Polymerase Inhibitor

Uridine PRODRUG = similar MoA as SOF

still in development

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Adefovir // Tenofovir

Adenosine Anologues

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

Prodrugs –> oral BV
activated by adenylate Kinase

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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

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Elbasvir

HCV NS5A Inhibitor

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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

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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

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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

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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** ## Footnote **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 ## Footnote ***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** ## Footnote **-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”**with**aromatic linker** in the middle