ANTI VIRAL CHEMOTHERAPY

SARATH T M AMRITA UNIVERSITY

DNA / RNA virus

Attachment Entry ( endocytosis / envelope fusion)UncoatingGenome replicationTranscription & TranslationAssemblyMaturationEgress ( cell lysis/ budding)Release

HIVAttachmentEntryUncoatingReverse transcriptionIntegrationTranscription& translationAssemblyBuddingMaturation

DNA VIRUS

HIV

INHIBITORS OF VIRAL UNCOATING

UNCOATING OF INFLUENZA -A VIRUS

INHIBITORS OF VIRAL GENOME REPLICATION

----NUCLEOSIDE ANALOGUES

ACYCLOVIR (ACV)

Against Herpes simplex virus (HSV/ HHV 1&2) & Vericella zoster (VZV/ HHV-3 )Inhibitor of viral DNA polymeraseHigh therapeutic indexGuanine base attached to an incomplete sugar ringDrug has to be activated to its triphosphate form

ACV

Acyclovir viral

Thymidine kinaseAcyclovir monophosphate

Acyclovir diphosphate

Cellular kinase

Acyclovir triphosphatecellular

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

viralDNA polymerase

Zidovudine (Azidothymidine) ( AZT )

Against HIVInhibitor of reverse transcriptaseThymidine base attached to a sugar in which 3’ OH is converted to an azido group

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

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

INHIBITORS OF VIRAL MATURATION

RITONAVIRInhibitor of HIV proteaseIn the long protein chain , a sequence of Phe-Pro is a site of cleavage for HIV proteaseAn unusual site of cleavage for human proteaseRitonavir is an analogue of this sequence in which Pro is replaced by PheInstead of C = O of peptide CHOH was used to mimic transition stateProteins formed are not processed efficientlyVirions that bud from infected cells remains immature & non-infectious