This presentation is prepared referring "Principles of Pharmacology" by David E Golan.

1. SARATH T M
AMRITA
UNIVERSITY

2. DNA / RNA virus
Attachment
Entry ( endocytosis / envelope fusion)
Uncoating
Genome replication
Transcription & Translation
Assembly
Maturation
Egress ( cell lysis/ budding)
Release
HIV
Attachment
Entry
Uncoating
Reverse transcription
Integration
Transcription&
translation
Assembly
Budding
Maturation

3. DNA VIRUS

4. HIV

5. INHIBITORS OF VIRAL UNCOATING

6. UNCOATING OF
INFLUENZA -A
VIRUS

7. INHIBITORS OF VIRAL GENOME REPLICATION
----NUCLEOSIDE ANALOGUES

8. ACYCLOVIR (ACV)
Against Herpes simplex virus (HSV/ HHV 1&2) & Vericella
zoster (VZV/ HHV-3 )
Inhibitor of viral DNA polymerase
High therapeutic index
Guanine base attached to an incomplete sugar ring
Drug has to be activated to its triphosphate form

9. ACV

10. Acyclovir viral
Thymidine kinase
Acyclovir monophosphate
Acyclovir diphosphate
Cellular
kinase
Acyclovir triphosphate
cellular
kinase
Incorporates into DNA
instead of dGTP opposite to a
C residue
(pppACV )
Chain termination
as pppACV has no
3’OH
Enzyme forms dead-end complex
with upcoming d-nucleoside
triphosphate---inactive enzyme
viral
DNA
polymerase

11. Zidovudine (Azidothymidine) ( AZT )
Against HIV
Inhibitor of reverse transcriptase
Thymidine base attached to a sugar in which 3’ OH is
converted to an azido group

12. AZT AZT
monophosphate
Cellular kinase
(HIV does not encode own kinase)
AZT diphosphate
Thymidylate
kinase
AZT triphosphate
RT
Chain termination, inactive
enzyme
cellular
No selectivity at
activation step (hence
toxicity is a serious issue)
Potent inhibitor of HIV
RT than human DNA
polymerase
Cellular nucleoside
diphosphate kinase

13. NNRTIs (Non-nucleoside analog RT inhibitors)
 As with the nucleoside analogs, the target enzyme is reverse
transcriptase.
However, NNRTIs bind directly and non-competitively to the
enzyme at a position in close proximity to the substrate binding site
for nucleosides. ( called as NNRTI pockets)
The resulting complex blocks the active site of the reverse
transcriptase.
This, in turn, can bind fewer nucleosides, slowing polymerization
down significantly.
In contrast to NRTIs, NNRTIs do not require activation within
the cell.
Eg: efavirenz

14. INHIBITORS OF VIRAL MATURATION

15. RITONAVIR
Inhibitor of HIV protease
In the long protein chain , a sequence of Phe-Pro is a site of
cleavage for HIV protease
An unusual site of cleavage for human protease
Ritonavir is an analogue of this sequence in which Pro is
replaced by Phe
Instead of C = O of peptide CHOH was used to mimic
transition state
Proteins formed are not processed efficiently
Virions that bud from infected cells remains immature & non-
infectious