Antiviral Drugs Flashcards
The most severe constraint limiting the use of antiviral drugs?
not the lack of efficacy but the toxicity to the mammalian cell (poor selective toxicity)
Virus specific enzymes
proteases, mRNA capping enzyme, neuraminidases, ribonucleases, kinases, integrases and uncoating enzymes
In the case of antivirals, the therapeutic window is
the ratio of the minimum dose that is toxic to host cells over the minimum dose that is toxic to the virus
What is required to maintain the suppression of many viral infections
an intact immune system (because antiviral drugs available so far are virostatic)
Three subclasses of drugs that prevent viral entry into host cells
- inhibitors of attachment that compete with a viral receptor
- coreceptor antagonists
- fusion inhibitors that prevent fusion with host cells
Maraviroc
CCR5 coreceptor antagonist - tested for AIDS treatment
what kind of patients should maraviroc be used in
CCR5-tropic patients (M-tropic)
When should maraviroc dose be adjusted
if used with drugs that inhibit or stimulate cytochrome P450 CYPA3 enzyme to adjust for changes in its metabolism
cenicriviroc
dual CCR5 and CCR2 antagonist
PRO 140
a CCR5 monoclonal antibody
for treatment experienced patients
Enfuvirtide (T-20)
fusion inhibitor
derived from the natural gp41 HR2 sequence
first HIV fusion inhibitor acting by specifically inhibiting the function of the gp41 transmembrane glycoprotein of HIV-1
Virus uncoating corresponds to
loss of viral protein coat (nucleocapsid proteins in nonenveloped viruses) or fusion of viral lipid memebranes (loss of lipid envelope in membrane containing viruses) with an endosome/lysosome
good target for therapy by interfering with pH?
endosome/lysosome compartment
Arildone
inhibits uncoating of picornaviruses that do not have a lipid membrane by blocking ion transport; drug inserts into a canyon in the VP1 viral proteins and blocks ion transport
What happens when you inhibit viral integrase?
prevent the insertion of the virus genetic code into the DNA of infected cells
Integrase inhibitors
Raltegravir (1st one)
elvitegravir, dolutegravir ect.
targets of drugs that act on the duplication of the viral genome
polymerases
nucleoside analog drugs
idoxuridine, cytarabine, vidarabine, ribavirin, acyclovir, ganciclovir, azidothimidine
Drugs that act on polyadenylation, methylation, capping, and splicing of viral RNA
ribavirin, interferon
Ribavirin inhibits
replication of DNA and RNA viruses including influenza A and B, RSV, hepatitis C, HIV
Ribozymes are
RNA molecules that induce specifically the cleavage of nucleic acids
Nonspecific drug that inhibits protein translation
interferon
What does neuraminidase or sialidase do?
helps spread the influenza virus from cell to cell by removing sialic acid from the surface of infected cells so that viral particles may escape
zanamivir is a potent inhibitor of
viral neuraminidase of type A and B influenza viruses
zanamivir acts as
a sialic acid analog inhibitor
highly specific for influenza viral neuraminidase and has little activity against mammalian/bacterial neuraminidases
Zanamivir requires
aerosol delivery to the respiratory tract
Oseltamivir
carbocyclic sialic acid analogue
Examples of drugs that interfere with the assembly of the molecular components into the whole virus
protease inhibitors
Examples of protease inhibitors
aquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir, darunavir, asunaprevir
Amantadine inhibits
uncoating of the viral RNA of influenza A
may act on the maturation stage of the virus in the trans-golfi network
acts on the maturation of influenza HA glycoprotein
Uses of Amantadine
oral prophylaxes against influenza A (not used much)
Side effects to Amandatine
GI intolerance and CNS complains (nervousness, difficulty concentrating)
Other drug related to amantadine
rimantadine
Idoxuridine is a pyrimidine analog that
inhibits viral DNA synthesis after activation by phosphorylation (by thymidine kinase)
idoxuridine is primarily active against
herpes and pox viruses
why is idoxuridine too toxic for systemic use?
lacks specificity: inhibits host DNA polymerase as well as the viral enzyme
What is idoxuridine used for?
topically for epithelial herpetic keratitis (mainly been replaced by other drugs)
What kind of drugs are cytarabine and vidarabine?
nucleoside analogs of cytosine and adeneine respectively
Ribavirin is a triazole purine nucleoside analog that inhibits
the replication of a wide range of RNA and DNA viruses in vitro
may act as a guanoside analog and inhibit 5’ cap formation on mRNA
Ribavirin used to treat
RSV in children
parainfluenza virus infections
IV against Lassa fever and other hemorrhagic fevers
orally to treat hepatitis C w interferon alpha
toxicity of ribavirin
high, notably dose-dependent hemolytic anemia
also mutagenic and teratogenic
Acyclovir
best example of multiple selectivity
very selective and one of the better antivirals
wide safety margins
Acyclovir is nontoxic to
noninfected cells (except for the kidney system since it induces renal dysfunction) because it is not activated by these cells
Acyclovir is what type of analog
purine analog that competes with dGTP
How does acyclovir block DNA synthesis
can block DNA synthesis by binding to the active site of DNA polymerase and inhibiting this enzyme
Triphosphate acyclovir also acts as a
chain terminator
Dosage adjustments of acyclovir required in case of
renal impairment (more than 70% of drug is excreted unchanged in urine)
resistant viral strains appear with acyclovir that result from
changes in the kinase or polymerase gene
Uses for acyclovir
HSV keratitis Varicella-Zoster virus latent HSV fever blisters genital herpes EBV/CMV
Drugs used to treat herpes simplex
acyclovir
valacyclovir
famciclovir
combination of acyclovir and hydrocortisone
Ganciclovir is very similar to
acyclovir
Uses of ganciclovir
restricted to life- or sight-threatening CMV infections in AIDS patients
Azidothymidine or zidovudine (AZT)
chain terminator
What accounts for the specificity of AZT?
reverse transcriptase is more sensitive to the drug than DNA-dependent DNA polymerase
AZT activity is enhanced by
acyclovir and interferon
AZT is very active against
mammalian retroviruses
HIV treatment
Side effects of AZT
mainly hematologic (granulocytopenia and anemia) some GI disturbance, paresthesia, skin rash, fever, abnormal liver function, myopathy
lamivurdine is very effect against
HBV
Adevofir is an analog of
adenosine monophosphate, competitively inhibits HBV DNA polymerase
Eight nucleoside reverse transcriptase inhibitors (NRTIs)
zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, tenofovir
Nucleotide reverse transcriptase inhibitor (NtRTI)
tenofovir, sofosbuvir
five non-nucleoside reverse transcriptase inhibitors (NNRTIs)
nevirapine, delavirdine, efavirenz, etravirine, and rilpivirine
Adenosine arabinosine
severe side effects and only used in potentially lethal diseases
Foscarnet (phosphonoformic acid)
competitive inhibitor of DNA polymerase that binds to pyrophosphate sites
also an inhibitor of RNA polymerase and HIV reverse transcriptase
Saquinavir
first protease inhibitor licensed for HIV therapy
used with ritonavir
Indinavir
reduces HIV load so that PCR can’t detect virus when used in combination therapy
intolerable side effects
Telapreir has been FDA approved to treat
Hepatitis C infection
Three classes of interferons
alpha, beta, gamma
what do alpha and beta interferons do
cytokines that bind to specific receptors on adjacent cells and protect them from viral infection also enhance the expression of class I and class II MHC
gamma interferon
cytokine secreted by T lymphocytes that enhances specific T cell mediated immune response
Side effects of interferons
fever, myalgia, bone marrow suppression, neurotoxicity
Pre-exposure prophylaxis for HIV
Truvada
