Viruses Flashcards
what are Viral polymerase/ Reverse transcriptase?
Essential enzymes that copy the genetic materials of the viruses
What are Limitations of Nuceloside analogues
Slow activation
Rapid deactivation
Active transport required
Can be toxic
MOA of Viral attachment inhibitors
Fostemavir targets the gp120 and prevents binding to the host CD4+
Maraviroc is a CCR5 antagonist that interferes with the binding of gp120 to CCR5
Palivizumab prevents RSV from infecting the host cell -> reduces viral replication and RSV spread
MOA of Viral penetration inhibitors
Enforvirtide is derived from gp4, mimics components of HIV-1 machinery. Binds to gp41 preventing fusion of HIV envelope with the host cell membrane
MOA of Viral uncoating inhibitors
M2 proton channel embedded in the viral envelope, virus enters cell via endocytosis
This activates M2, leading to proton influx -> particle dissociation and viral genome release
Amantadine binds and blocks M2 channels in the lumen -> no proton influx
MOA of Nucleos(t)ide inhibitors
Inhibit viral polymerase by competing with the natural substrate
Are incorporated into the growing nucleic acid chain and terminate elongation
Must be activated by phosphorylation by host/kinase (triphosphate)
MOA:
Chain termination: Lack a 3’ OH -> no further incorporation events or 3’ OH present and extra groups at 2/4 -> steric hindrance incorporation of NTP
Mutagenesis: Introduce wrong nucleotide -> genome mutations
MOA of Non-Nucelotide analogues
Bind to viral polymerase at an allosteric site adjacent to substrate binding site
Binding inactivates enzyme conformation -> catalyst function indirectly inhibited
Do not need activation/phosphorylation
MOA of Viral transcription inhibitors
Influenza
PA endonuclease is essential to initiate viral RNA synthesis
Baloxavir acid inhibits PA endonuclease -> prevents transcription and replication
MOA of Integrase inhibitors (HIV only )
Retroviruses produce enzyme intergase (allows integration of viral DNA into host cell DNA)
Inhibitors block the strand transfer step of HIV DNA integration into human cDNA by chelating essential mg2+ cofactor at catalytic site
MOA of Viral protease inhibitors
Selectively bind to viral proteases, reversibly blocking proteolytic cleavage of polyprotein precursors
HIV:
- Competitive inhibitors bind to active site
- Bind stronger than substrate
- Contains various non cleavable groups
MOA of Viral release inhibitors
Neuraminidase inhibitors (influenza)
Neuraminidase inhibitor’s are synthetic analogues of sialic acid
Enzymes located on influenza virus envelope
Disrupts binding between hemagglutinin and sialic acid during budding
New virons released -> viral spread
Block enzyme site completely -> no release from host cell
what are the stages of the Virus life cycle ?
- attachment
- penetration
- uncoating
- synthesis
- maturation/assembly
- release
Give examples of HIV antivirals (6)
NRTI
NNRTI
Integrase inhibitors
fusion inhibitors
attachment inhibitors
protease inhibitors
Why use Antiviral combination therapy
Risk of resistance in monotherapy
Combination of antivirals with different MOA and synergy effect on HCV, HIV
Advantages: Delays resistance, strengthens potency, reduced dose (less toxicities), improved adherence
How does Antiviral resistance occur?
During genome replication, spontaneous errors occur
Reversible transcriptase and RNA polymerase are error prone (no proof reading)
High replication rate results in large genetic variability
