Anti-Viral Drugs Flashcards
for what virus are the following drugs all used for, and what classes do they belong to, respectively?
a. remdesivir
b. nirmatrelvir
c. tixagevimab/cilgavimab
d. bebtelovimab
all anti-virals for SARs-CoV-2
a. remdesivir - nucleoside analog
b. nirmatrelvir - protease inhibitor
c. tixagevimab/cilgavimab -mAb
d. bebtelovimab -mAb
what kind of drug is acyclovir, and what kinds of viruses is it used against? name 2 specific viral infections it treats
acyclovir: nucleoside analog of guanosine, used to treat DNA viruses
- Herpes Simplex (HSV)
- Varicella Zoster (VZV)
how does acyclovir work?
acyclovir: nucleoside analog of guanosine, binds viral DNA pol and inhibits replication (chain terminator)
note acyclovir gets its first phosphate from a viral enzyme HSV-1 TK (thymidine kinase) - if enzyme mutates, drug stops working
(di- and tri- phosphorylation by host enzymes)
what feature of acyclovir makes it specific for virally infected cells but also susceptible to mutational resistance?
acyclovir: nucleoside analog, competes with dGTP to bind viral DNA pol and chain terminate
recall nucleoside analogs are taken as prodrugs and phosphorylated after entry into cell, because phosphates negative charge would prevent transport into the body, and that phosphorylation traps drug within the cell
acyclovir mono-phosphorylated by viral HSV-TK (tyrosine kinase), so it only gets trapped inside infected cells that need it!… however, viral mutation in HSV-TK renders drug ineffective :(
explain why nucleoside analogs are taken as prodrugs
prodrugs lack phosphates necessary for DNA synthesis
but phosphates neg. charge would pre vent transport into the body
so prodrugs enter cell, then are phosphorylated
phosphorylation also traps drug inside cell, adding to efficacy
Valacyclovir
derivative of acyclovir (nucleoside analog of guanosine, viral DNA replication inhibitor)
valacyclovir has valine protective group added to increase oral bioavailability
what kind of drugs are acyclovir (/valacyclovir) and ganciclovir (/valganciclovir)? what viruses are the used for?
nucleoside analogs, function as chain terminators in viral DNA replication - so used for DNA viruses
these are used for HSV, VZV, and CMV
valacyclovir/valganciclovir have valine protective group added for increased bioavailability
what kind of drug is letermovir and how does it work?
letermovir: anti-viral drug for DNA virus (cytomegalovirus/CMV), decatenation inhibitor
blocks cleavage of viral concatemers (long chain of viral DNA) into monomers —> blocks viral packaging
what are the drug interactions of letermovir, anti-DNA virus drug?
letermovir: blocks cleavage of cytomegalovirus (CMV) DNA into monomers for packaging
inhibitor and inducer of CYP3A and other P450 enzymes
also inhibits renal drug transporters
what kind of drugs are oseltamivir, zanamivir, and peramivir? how do they work?
Neuramidase (NA) inhibitors of influenza virus (A and B) —> prevent NA-mediated cleavage of sialic residues on cell surface and subsequent virion exit from cell
note that these prevent viral spread but do not deactivate virus, so they are bacteriostatic in a sense (but for virus) - considering this, it makes sense that anti-influenza drugs do not work immediately, but rather shorten duration of illness (and reduce risk of complications)
Oseltamivir = Tamiflu
what kind of drug is baloxavir marboxil and how does it work?
baloxavir marboxil: anti-influenza (neg. RNA) drug, mRNA cap-snatching inhibitor
recall that influenza uses viral RNA-dep. RNA pol. and RNAs lack 5’-cap (7-methylguanosine) necessary for translation in humans
influenza endonuclease “steals” human mRNA caps to initiate viral transcription
[“Baloxavir Marboxil” just sounds like the name of a snatching burglar]
what kind of drug is sofosbuvir and how does it work?
sofosbuvir: anti-HCV (hep. C, +RNA) drug, nucleoside analog of uridine
chain terminator of NS5B RNA-dep. RNA pol. gene via fluorine-mediated steric hindrance
phosphorylated pro-drug (overcomes rate-limiting kinase rxn), protecting groups removed in cell
part of ALL oral treatment for HCV!
what kind of drug are glecaprevir, grazoprevir, and voxilaprevir, and how do they work?
anti-HCV (hep. C, +RNA) drugs that inhibit NS3/4A serine protease via binding active site (reversibly)
NS3 = catalytic subunit, NS4A = cofactor —> cleave HCV polyproteins
Glecaprevir: requires only 8 wk treatment
what kind of drug are pibrentasvir, ledipasvir, velpatasvir, and elbasvir? how do they work?
anti-HCV (hep C, +RNA) drugs, block NS5A dimer protein - lacks enzymatic activity but required for RNA replication and packaging
no human homolog for NS5A makes it good drug target
Pibrentasvir: requires only 8 wk treatment, effective for all genotypes
[pi-Ha-brenta-Csss-Vir = HCV!]
what is the goal of HBV (Hep B, DNA virus) treatment? What is considered first line, and what is a major barrier to this treatment?
HBV treatment primarily to reduce morbidity/mortality - nuclear viral DNA remains even when viral antigens undetectable
PEG-IFN is considered first-line but treatment often stopped early because of many adverse effects (thrombocytopenia, neurotoxicity, autoimmunity, hepatotoxicity, etc…)
nucleoside analogs also considered first-line and have fewer associated side effects/restrictions
how are interferons (IFN) used in treatment of HBV (Hep B, DNA virus)?
IFNs: human antiviral proteins (alpha, beta, gamma), signal via JAK-STAT pathway —> enhanced CTL, transcription/translation/protein processing inhibition, etc
link IFN to PEG (polyethylene glycol) to increase half-life - allows for less frequent injections
PEG-IFN + ribavirin = standard protocol for 48 week treatment
*note IFN have MANY adverse effects and reduce P450 metabolism of other drugs
how does HBV genome replicate, and how can this be exploited in anti-viral therapy?
HBV: DNA genome, replicates through RNA intermediate
virion contains relaxed circular DNA (rcDNA) which is converted to covalently closed circular DNA in nucleus, which is THEN transcribed into a long pre-genomic RNA (pgRNA), which is THENN converted to rcDNA by HBV RT
nucleoside analogs (Tenofovir or entecavir) binds RT and chain terminates
what kind of drug is tenofovir and how does it work?
tenofovir: anti-HBV drug, nucleoTIDE analog for adenosine
contains first phosphate (overcomes rate-limiting step) and protective group is stripped in plasma before cell entry
binds HBV RT (HBV is DNA virus that replicates through RNA intermediate) —> chain terminates
few drug-drug interactions
what kind of drugs are Remdesivir and molnupiravir and what are they used for?
anti-SARs-CoV-2 nucleoside analogs
Remdesivir:
- adenosine analog, causes chain termination downstream of incorporation site (delayed), disrupts structure of RNA:RNA duplex
- carries first phosphate, has protecting group
- originally developed for HCV
- IV administration
What kind of drug is nirmatrelvir and how does it work?
nirmatrelvir: protease inhibitor for SARs-CoV-2 (needed to cleave viral polyprotein)
reversible inhibitor that covalently links! (unusual) binds catalytic cysteine
packaged with ritonavir (Paxlovid) to slow metabolism by P450
*very effective but note high incidence of viral rebounding following drug use
what are tixagevimab/cilgavimab and bebtelovimab used for?
mAb for Sars-CoV-2, neutralize spike protein
tixagevimab/cilgavimab: combo, for pre-exposure prophylaxis, LONG acting (6mo), less neutralizing against Omicron, IM injection
bebtelovimab: effective against Omicron, single IV infusion
