antiviral agents Flashcards
what do antivirals target?
viral replication
what are good potential antiviral drugs?
Molecules that are virus encoded ofer potential virus-specific targets. This is notably the
case with viruses that have large genomes and code for their own replicative enzymes.
what is the main issue with using antivirals?
Therefore the most severe constraint limiting the use of antiviral drugs is not the lack of eficacy but he toxicity to the mammalian cel (por selective toxicity).
-viral replication is intimately associated with host replication
what defines a good antivirals
1.) successful antiviral drug should interfere with a virus-specific function (either because the function is unique to the virus or the similarhost function is much less
susceptible to the drug). Virus specific enzymes include proteases, mRNA caping enzyme, neuraminidases, ribonucleases, kinases, integrases, and uncoating enzymes
2.) successful antiviral drug should interfere with a virus-specific function (either because the function is unique to the virus or the similar host function is much less
susceptible to the drug). Virus specific enzymes include proteases, mRNA caping enzyme, neuraminidases, ribonucleases, kinases, integrases, and `uncoating enzymes
target therapeutic index
100-1000
- ratio of the minimum dose that is toxic to
host cels over the minimum dose that is toxic to the virus
ideally antiviral should
should be stable in the blood stream and easily taken by cells.
-They should also have as low toxicity as posible
successful antivirals
interferes with virus specific function or with a function for which the host target is less susceptible to the drug
what is virostatic
doesn’t kill virus
what does it mean that antivirals are virostatic?
must have an intact immune system to maintain the suppression of many viral infections
potential targets of drugs
- ) prevention of entry into host cells
- ) inhibition of virus uncoating
- ) integrase inhibitors
- ) duplication of viral genome
- ) mRNA transcription and processing
- ) protein translation
- ) post-translational modification of proteins
- ) assembly of molecular components into whole virus, maturation
- CCR5 co-receptor antagonist maraviroe
prevention of entry into host cells
- CCR5 co-receptor antagonist maraviroc
- can be used to treat in CCR5 tropic patients
- adjust dosage if combined with drugs that influence CYP enzymes
- one of the drugs being considered for preventive treatment against HIV infection
- exist non-competitive resistance by HIV: uses drug-bound form of CCR5 as a co-receptor
fusion inhibitors
Enfuvirtide
- inhibits HIV-specific gp-41 transmembrane glycoprotein
- used for patients not responding to current therapy
uncoating of virus consist of
loss of nucleocapside
what is noncompetitive resistance
when a virus learns to use a drug-bound form of receptor -example: maraviroc
when is un-coating pH-dependent?
at low pH, at level of endosomes or lysosomes
when is un-coating pH-independent?
when fusion with the plasma membrane
what is the best class of selective drugs available?
duplication of viral genome (RNA, DNA)
- act on duplication of viral genome, polymerases
- these drugs are mainly nucleoside analogs
why makes duplication drugs so selective?
- ) virus may use its own enzymes to activate the drug
2. ) viral polymerases are much more sensitive to drug than the corresponding host enzyme
what activates drugs in the duplication of viral genome class?
thymidine kinase encoded by some viruses-> used for synthesis of their DNA
- can activate certain drugs of this class
- leads to SELECTIVITY for infected cells only
what does the lack of selectivity for viral thymidine kinase allow?
allows nucleoside-analog drugs to be phosphorlyated like endogenous nucleosides
-enzyme of host cell have much greater specificity and it often does not phosphorylate the drug
why can nucleoside analogs enter the cell?
viral thymidine kinase can phosphorylate the nucleoside analogs permitting administration of drug in nonpohosphorylated form-> can enter cell better
how do nucleoside analog drugs cause chain termination?
-once the nucleoside analog is phosphorylated by thymidine kinase-> then by host cell’s enzymatic machinery-> formed into triphosphate compound-> incorporated into the growing nucleic acid chain-> leads to an irreversible association with viral polymerase and chain termination
nucleoside analog drugs
idoxuridine, cytarabine, vidarabine, ribavirin, acyclovir, ganciclovir, azidothimide
integrase inhibitor drugs
elvitegravir, dolutegravir, raltegravir (used to treat AIDS)
integrase inhibitors MOA
prevent insertion of virus genetic code into the DNA of infected cells by inhibiting the viral integrase
-Integrase strand transfer inhibitors-> used to treat AIDS
inhibition of un-coating drugs
arildone, plecoranil, amatidine, rimantidine
mRNA transcription and processing drug MOA
act on polyadenylation, methylation, capping and splicing of viral RNA
-can act as guanosine analogs and inhibit 5’ capping
mRNA transcription and processing drugs
ribavirin (inhibits DNA/RNA replication) , interferon
what are riboenzymes? what class of drugs do they belong with?
- RNA molecules that induce specifically the cleavage of nucleic acids (heptazyme-> cleave hep C RNA)
- mRNA transcription and processing drugs
post translational drugs
interferons
post-translational modification drugs MOA
- interfere w/ glycosylation, phosphorylation, fatty acylation
- Neuraminidase (NA) or sialidase helps spread infleunza from cell to cell by removing sialic acid from surface of infected cells ->viral particles can escape
post-translation modification drugs
zanamivir (inhibitor of NA), oseltamivir (inhibitor of NA, activated in gut and liver)
-N&V side effect
what does zanamivir require?
aerosol delivery to respiratory tract
protease inhibitor need to know
indinavir
Amantadine MOA
inhibits un-coating of viral RNA of influenza
- lysosomotropic
- maybe act on Golgi-network
- real action: maturation of influenza HA glycoprotein-> decreases infective potential of virus progeny
- eliminated in urine unchanged
use for amantadine
oral prophylaxis against influenza A
-alternate vaccine in IC’s and elderly
side effects of Amantadine
GI intolerance, CNS complaints
better drug than amantadine
rimantadine
-less toxic
first generation antiviral nucleoside analog
idoxuridine
-pyrimidine analog
MOA of idoxuridine
inhibits viral DNA synthesis after activation by phosphoylation by thymidine kinase
-active against herpes and pox viruses
why is idoxuridine so toxic? How is it ONLY use?
lacks specificity
- inhibits host DNA polymerase as well as virus
- used topically, for epithelial herpetic keratitis
acyclovir is
VERY SELECTIVE
-one of better antivirals
why is acyclovir so selective?
nontoxic to noninfected cells because is not activated by these cells
MOA of acyclovir
activated by herpes virus thymidine kinase-> activation converts to monophosphate-> rate of conversion very fast in infected cells-> binds with high affinity to viral enzymes more than host-> second and third PO3 preformed by host
Acyclovir is what kind of analog?
purine analog
- competes with dGTP
- once phosphorylated and incorporated into DNA-> blocks DNA synthesis by binding to active site of DNA polymerase and inhibits it.
- also acts as chain terminator (triPO3)-> remains bound to polymerase-> polymerase inhibition
administration of acyclovir
IV, topically, per os
what is major consideration when administering acyclovir IV?
tissue irritation if extravasation occurs
-N&V otherwise side effect
how is acyclovir clear?
kidneys
-dosage adjustment if renal impairment
use for acyclovir
EBV, herpes simplex keratitis, chicken pox, HSV, fever blisters, genital herpes, CMV
azidothymidine (AZT) drug classification
chain terminator
-prodrug
what kind of viruses is AZT used for?
- phosphorylated by cells kinase-> used against viruses that do not have their own kinase
- phosphorylation required to become active
what accounts for AZT specificity?
reverse transcriptase is more sensitive to drug than DNA dependent DNA polymerase
what enhances AZT use?
acyclovir and interferon
side effects of AZT
hematologic-> anemia GI disturbances paresthesia skin rash fever abnormal liver function myopathy
why shouldn’t AZT be taken with aspirin, acetaminophen or indomethacin?
if used with a drug that interacts with the glucuronyl transferase pathway
use of AZT
HIV treatment
antivirals used in treatment for HIV
Indinavir, AZT, maraviroc, saquinavir, ritonavir, amprenavir, darnavir
different classes of interferons?
alpha, beta, gamma
alpha and beta interferons MOA
cytokines that secreted by virus infected cells
- bind specific receptors on adjacent cells and protect them from viral infection
- enhance expression of class I and class II MHC molecules on surface of infected cells-> enhances phenomenon of presentation of viral antigens to specific immune cells
gamma interferons MOA
cytokine secreted only by T-cells in response to antigen
-enhances specific T cell mediated immune response
what do interferons do to RNA and DNA virus replication?
- ) enhance specific immune responses
- ) direct antiviral effects including viral penetration or uncoating, stimulation of degradation of viral mRNA, inhibition of synthesis or methylation or mRNA and inhibition of protein synthesis
how must interferons by administered?
IV or IM
-not active if given orally
examples of pre-exposure prophylaxis
Truvada
amantadine
rimantadine
NA inhibitors: zanamivir and oseltamivir
pre-exposure prophylaxis
PrEP
-only used in individuals who are HIV negative
used in combination with protective sex practices
influenza PrEP
osetlamivir (tamiflu) (1 year old)
Zanamivir (5 years old)-> not be used with people with underlying respiratory disease
