Antivirals Flashcards
What are some challenges with designing antivirals?
- shutting down viral machinery = shutting down the cell – toxicities are unacceptable
- some medically important viruses are not safe to propoagate (e.g. ebola) or have no good animal model (e.g. HBV)
- a drug must sufficient;y suppress/treat or the virus to either clear or lower it until the immune system can take over
Name 7 possible antiviral targets
- viral attatchment
- cell entry
- uncoating
- transcription
- translation
- viral assembly
- viral release
why is acylovir important for treating HSV encephalitis?
reduces mortality by >50% to 8-30% (depends on timining of initiation and risk factors)
what type of antiviral is acylovir?
acyclic nucleoside analogue of guanosine
what is the mechanism of action of acyclvoir?
- tri-phosphorylated by cellular kinases to ACV-TP: first phosphorylation via viral thymidine kinase and subsequent phosphoylation via celluar kinases which are upregulated is HSV-1 infected cells
- inhibits viral DNAP and obligate DNA chain termination
which viruses does acyclovir work against?
- HSV
- VZV
- in vitro activity agasint EBV
if you were HSV-1 how could you avoid the effects of ACV?
mutate (change or away) HSV-1 TK and/or viral DNAP
in which population is there more resistance to acyclovir, what are the mechanisms (state which are the most common vs least common)?
resistance is more common in immunocompromised patients
mechanism - most common to least
- absent or reduced TK – cross-ressitance to other agents that require TK activation, but have decreased virulence
- altered TK
- viral DNAP mutations
why can’t acyclovir be used against CMV? which drug can?
CMV does not have a viral thymidine kinase, but it has a phosphotransferase kinase (PK; does first phosphorylation of drug) – glanciclovir is much more potent
which viruses can be treated by glanciclovir? what are the routes of administration?
viruses
- CMV
- EBV
- HSV/VZV
- human herpesvirus 6?
routes
- oral
- IV
- intraocular
what are the resistance mechanisms to glanciclovir? how can we counteract these mechanisms?
resistance
- mutation in PK
- mutation in DNAP
counter attack
- already have one phosphate group attatched to the drug
- add hydrophobic chain to phosphate –> better absorption
foscarnet (PFA): what is its classification, mech of action, viruses it can be used to treat?
classification
- inorganic pyrophosphate analogue
mechanism of action
- inhibit viral DNAP – inhibits pyrophosphate cleavage from dNTPs
- inhibit viral reverse transcriptase
indications
- HSV
- retrovirses: HIV
- HBV
what is the classification of saquinavir? how does it broadly work in the context of HIV?
protease inhibitor – prevents cleavage of viral polyprotein to individual proteins
what does the HIV protease do?
cleaves N-terminal to Pro (something human endoproteases don’t do)
how was saquinavir developed? what is this called?
- quantitative structure-activity relationship (QSAR)
- molecular modeling and docking studies
- ligand-based design
rational drug design
