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Flashcards in Antiviral Drugs Deck (21)
1

Viruses treatable with drugs

-DNA- Herpesvirus (Acyclovirs), Hep B
-RNA- Influenza, Hep C (Ribavirin). HIV

2

Types of antiviral treatment

-virucidal- detergents, cryotherapy
-immunomodulatory- alpha-interferon
-antiviral

3

Types of antivirals

-Nucleoside analogs ("Nucs")
-Non-nucleosides ("Non nucs")
-Protease inhibitors
-entry inhibitors
->50 antiviral drugs are in use, more in the pipeline

4

How do antiviral drugs work?

-target essential virus functions- entry, genome replication, assembly, release from cell
-target host cell defenses (intrinisic immunity)-interferon pathway
-activate immune response (closer to vaccines)

5

Antiviral drugs and places of attack

-viral entry- (against HIV) enfuvirtide
-viral uncoating- (against influenza A)- Amantadine- Resistance
-Nucleic acid synthesis (against herpesviruses ad HIV)- nucleoside analogs, non-nucleoside polymerase inhibitors
-Assembly and release of viral particles (against HIV)- protease inhibitors, (against influenza)- neuraminidase inhibitors

6

Nucleotide synthesis pathways

-many antivirals are nucleoside analogs that compete for the enzymes in the purine and pyrimidine synthesis pathways
-viral enzymes are also involved
-herpesvirus thymidine kinase is used to increase the pool of dTTP in infected cells
-acyclovir is a substrate of viral TK and takes place of thymidine
-acylcovir-triphosphate is incorporated into viral DNA in place of dTTP

7

Important Issues about Antivirals

-Specificity- most drugs target functions of only one virus, broad spectrum drugs are rare

-Cytotoxicity- off target effects can harm cells, on target drugs directed at viral enzymes can be defeated by resistance mutations

-Duration of antiviral effects- most drugs are reversible (competitive inhibitors), virus replication can resume when drug is cleared (REBOUND), treatment might need to be lifelong

8

Resistance to Antivirals

-resistance mutations often exist in patient before drug treatment
-drug treatment selects for resistant virus strains
-factors favoring the emergence of resistant variants- high rate of virus replication, high mutation rate (RNA>> DNA), high selective drug pressure, immunosuppressed host that cannot clear virus infected cells

9

How do we counter resistance to antivirals

-alleviate immunosuppression in the treated person- lower doses of anti-T cell drugs (steriods, cyclosporin, etc)
-combine drugs with different targets- standard of care for HIV and HCV infections, drugs with different mechanisms of action synergize, lower probability that multiple resistance mutantions will be present
-target host functions- infected cells may have unique profile that can be a drug target, virus mutations do not impact cellular genes, some cancer drugs target dividing cells and also inhibit viruses, beware of toxicity

10

Treatments for HSV-1, HSV-2, and VZV

-who should be treated- acyclovir
-neonates infected with HSV at birth
-people with frequent recurrences (type 1 and 2)
-complicated HSV infections: encephalitis, dissemination throughout body, eye infections
-people with zoster (within 3 days of appearance of rash)

11

Acyclovir

-nucleoside analog of guanosine
-effective against- HSV-1= HSV-2 >> VZV
-trade name: Zovirax
-derivatives- Valaciclovir=Valtrex, Penciclovir=Denavir, Famciclovir=Famvir
-there is a viral thymidine kinase that phosphorylates, then there are host kinases, then there are viral DNA polymerase

12

Ganciclovir for CMV

-ganciclovir is nucleoside analog for guanosine
-ganciclovir= cytovene, derivative: valganciclovir- Valcyte
-similar mechanism of action to acyclovir
-highly toxic- suppresses bone marrow mutagenic and teratogenic, severe side effects
-who should be treated?
-bone marrow and organ transplant patients
-immunosuppressed people with active CMV
-CMV retinitis

13

Broad Spectrum Treatments for DNA viruses

-Foscarnet=Foscavir
-trisodium phosphonoformate
-inhibits viral DNA polymerase
-effective against all herpesviruses
-IV route only, toxic to kidneys

-Cidofovir=Vistide
-nucleoside analog of cytosine
-effective against DNA viruses: herpesvirus, adenovirus, papillomavirus, poxvirus, IV route only, toxic to kidneys

14

Treatments for Hep B

-HBV is treated with drugs designed for HCV and HIV
-current drug options:
-pegylated interferon alpha= Pegasys
-entecavir= baraclude
-tenofovir disoproxil fumarate= Viread

-who should be treated?
-people with chronic active HBV disease
-people co-infected with HCV and/or HIV
-people who are progressing to cirrhosis, liver failure, or hepatocellular carcinoma

15

Treatments for Influenza

-Zanamivir= Relenza, Oseltamivir= Tamiflu
-both are sialic acid analogs that inhibit viral neuraminidase (sialidase)
-virions remain attached to cell

-who should be treated?
-the severely ill (hospitalized)
-children younger than 2
-adults over 65
-pregnant women
-immunosuppressed people
-anyone suspected of having influenza

16

Ribavirin "Borad Spectrum"

-nucleoside analog of guanosine
-oral, IV, and aerosol formulations
-approved for use against HCV and RSV
-off-label use: HSV, influenza, SARS, La Crosse encephalitis, Nipah encephalitis, Lassa fever, Hemorrhagic fever with renal syndrome, Crimean-Congo hemorrhagic fever, Bolivian hemorrhagic fever, Hantavirus pulmonary syndrome

17

Treatments for Hep C Virus

-combination therapy Peg interferon alpha with ribavirin
-not all HCV genotypes respond to drugs
-difficult and complicated treatment regimen- flu-like symptoms, anemia, neutropenia and thrombocytopenia, rashes, hair loss, thyroid dysfunction, depression and fatigue, irritability and mania

18

Treatments for HIV

-AZT= Zidovudine was the first drug for HIV, now an antique
-nucleoside analog of thymidine
-NRTI class (Nucleoside Reverse Transcriptase Inhibitor)

19

Classes of anti-HIV drugs

-Entry inhibitor- Maraviroc-Selzentry
-NRTI (Nucleoside/tide RT inhibitor)-Tenofovir- Viread
-NNRTI (Non-nucleoside RT inhibitor)- Efavirenz= Sustiva
-IN (Integrase inhibitor)- Raltegravir= Isentress
-PI (protease inhibitor)- Darunavir= Prezista

20

Stribild for HIV

-4 Drug Combination- Elvitegravir- Integrase, Cobicistat- Liver enzyme, Emtricitabine- RT, Tenofovir disoproxil fumarate- RT
-What is cobicistat? A drug enhancer
-inhibits CYP3A4 that breaks down drugs in the liver
-Cobicistat treatments boosts the potency of elvitegravir
-this allows fewer pills or doses (one pill)

21

Final Thoughts on Antivirals

-new drugs are always needed-resistant variants, new viruses, diseases without treatment options
-infectious disease specialists are super helpful- complex treatment plans for HBV, HCV, HIV, organ transplant patients
-translational research is hot- bench to beside theory works for antivirals
-NCATS: National Center for Advancing Translations Sciences is newest center at NIH