Antiviral Chemotherapy 1 (DONE) Flashcards
Characteristics of viruses
Small Parasites Rely on host enzymes to proliferate Contain either DNA or RNA Proliferate by replication
Viral Replication
This is the unique process by which viral particles proliferate
All viral particles need a host cell (human, animal, plant or bacterial) in which to replicate
Steps of viral replication
Random collision Attachment Viropexis (engulfment) Uncoating Nucleic acid synthesis Protein synthesis Assembly Release In theory, each step could be the target for an antiviral
Viral encoded enzymes vs host targets
It is possible to have an antiviral effect by targeting the viral encoded proteins or host (cellular) enzymes/factors used by the virus
Host target has low resistance and broad spectrum but possible toxicity
Viral target has selective agents and limited toxicity but resistance
Nucleosides as analogues mechanism of action
All nucleoside drugs require metabolic activation in their target cell to the bio-active phosphate forms
Nucleosides can be phosphorylated by host or viral kinases if present, viral is faster because it is less selective
Acyclovir
Unusual acyclic sugar moiety
Mechanism of action: phosphorylated by viral TK then by kinases to the active triphosphate form
Inhibition of viral DNA polymerase by ACGTP
Causes faulty viral DNA
Valacyclovir
Due to the poor oral bioavailability of acyclovir, for oral use it is formulated as its prodrug valacyclovir (Valtrex)
This was the top selling antiviral in 2008 with sales of almost $1.7Bn
ACG analogues
The major success of ACG lead to the search for improved analogues. A number have emerged: ganciclovir, penciclovir, famciclovir
AZT
The emergence of HIV infection and AIDS during the 1980s lead to a huge interest in new (and old) nucleoside analogues as possible anti-HIV agents. An old compound, AZT, emerged as the initial lead drug.
This is based on thymidine, but with a modification at C3’. In particular, the OH group of thymidine is replaced by an azido (N3) group
AZT: differences with acyclovir and valacyclovir
Follows similar lines to acyclovir and valacyclovir, with two major differences: The virus does not specify its own TK, so this cannot be used for selective activation of the drug. The virus (HIV) does contain a unique, essential viral enzyme; a reverse transcriptase, which builds a viral DNA chain upon a viral RNA template. This is considered to be an ideal target for selective anti-HIV action.
AZT: Mechanism of action
Host kinase mediated phosphorylation to the active triphosphate form
Inhibition of HIV RT by AZTTP
Possibly also assisted by incorporation into viral DNA and consequential chain termination
AZT: analogues
A number of other compounds have now emerged as anti-HIV agents which might be regarded as AZT analogues
Aryl BCNAs
We have discovered aryl BCNAs as the most potent and selective anti-VZV agents reported to date.
The BCNA Cf1743 is the most potent inhibitor of VZV ever reported. It is ca 10,000 times more potent than ACV, and is entirely VZV specific.
It is non-toxic at 100 micromolar and has S.I. of 1,000,000
VZV MoA
VZV TK phosphorylates to the active triphosphate form. VZV thymidine kinase is essential for anti-viral activity- explains the utter VZV selectivity of the BCNAs.
Problems of nucleoside drugs
Often poor metabolism to the active triphosphates
Rapid deactivation
Active transport needed
Toxicity common
Emergence of resistant virus (tumour)- transporter, kinase, polymerase
