Neamati Hiv

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retroviral enzymes

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1) RT
2) protease
3) integrase

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RT activ

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RNA dependent DNA polymerase
RNAse H activ
DNA dependent DNA polymerase

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RNA dependent DNA polymerase

Back 3

converts ssRNA genome to dsRNA:DNA hybrid

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RNAse activ

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hydrolizes RNA strand of dsRNA:DNA hybrid to generate ssDNA complementary to RNA genome of virus

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DNA dependent DNA polymerase

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converts ssDNA to dsDNA

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NRTI's are prodrugs - why?

(nucleoside reverse transcriptase inhibitors)

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the prodrug has low cytotoxicity prior to activation. (redox)

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Common features of NRTI's
(nucleoside reverse transcriptase inhibitors)

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sugar base; H2O solubility;
not substrate for CYP (cytochrome 450) and P-glycoprot

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P-glycoprot
CYP

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efflux pump (cytotox from MultiResistant cells)
liver detox

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Mechanism of anti-HIV activity of NRTIs and ANPs

(acyclic nucleoside phosphonates)

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DNA chain termination after they are incorporated into DNA

Competition with the natural dNTP substrates to be incorporated into growing DNA chain

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Structures of NNRTIs
(non-nucleoside revers. TI)

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hydrophobic molecules
metabolized by CYP3A4

Highly selective against HIV-1 strains (1000x more selective than AZT

Interact with a nonsubstrate binding site at HIV-1 RT

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NNRTIs

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do not have typical nucleoside structure

do not need to be metabolized in the cell to display antiviral activity

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BOTH NRTI and NNRTI target RT.

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NRTI directly interacts with dNTP substrate binding site, NNRTI interact with nonsubstrate binding site at HIV-1 RT

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incorporation

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NRTIs incorporate in growing viral DNA chain and act as DNA chain terminators.

NNRTIs are not incorp. in vDNA

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select for HIV1 strains

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both NRTI and NNRTI select HIV1 strain but AA changes in RT are diff

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NRTI/NNRTI interact w/ cellular DNA polymerases.

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NRTI

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catalytic activities of integrase

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3'-processing
strand transfer

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3'-processing

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endonuclease
"cut vDNA"
cytoplasm

2 deoxynucleotides are removed from 3'-end of vDNA

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strand transfer

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integration
"paste vDNA into host DNA"
nucleus