Biochemical and mechanistic basis for the activity of nucleoside analogue inhibitors of HIV reverse transcriptase.
HIV encodes an RNA directed DNA polymerase (reverse transcriptase, RT) that is an essential enzyme in the viral replication cycle. This enzyme catalyzes the synthesis of double stranded proviral DNA from single stranded genomic RNA via a bireactant-biproduct mechanism. The functional enzyme purified from virus particles is a complex consisting of two polypeptides of molecular weight 66,000 and 51,000. Two of the four classes of currently approved anti-HIV drugs, the nucleoside reverse transcriptase inhibitors (NRTIs) and the non-nucleoside reverse transcriptase inhibitors (NNRTIs), act by inhibiting this enzyme. In this review each step of DNA synthesis catalyzed by the RT is described and the mechanism of inhibition of catalysis and termination of DNA synthesis by NRTIs is detailed. The individual steps in the catalytic cycle and the effects that the NRTIs have on them have been examined using transient kinetic analysis. The impact of stereoisomerism and resistance mutations on the rate of NRTI triphosphate incorporation (k(pol)), binding in the catalytic complex (K(d)) and the overall efficiency of incorporation (k(pol)/K(d)) are summarized for lamivudine, coviracil and zalcitabine. The results provide insight into the molecular forces and structural features that make these molecules effective inhibitors.
Painter
George R
GR
Chimerix, Inc., 5007 Southpark Dr., Suite 200, Durham, NC 27713, USA. gpainter@chimerix-inc.com.
Almond
Merrick R
MR
Mao
Shuli
S
Liotta
Dennis C
DC
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D003570:Cytidine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D003843:Deoxycytidine Monophosphate / Q000031:analogs & derivatives / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000378:metabolism; D004148:Dioxolanes / Q000494:pharmacology / Q000627:therapeutic use; D000068679:Emtricitabine; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D011684:Purine Nucleosides / Q000494:pharmacology / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013379:Substrate Specificity; D000068698:Tenofovir; D016047:Zalcitabine / Q000031:analogs & derivatives
D004279:DNA, Viral; D003854:Deoxyribonucleotides; D004148:Dioxolanes; D009705:Nucleosides; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011684:Purine Nucleosides; D018894:Reverse Transcriptase Inhibitors; D003841:Deoxycytidine; D003843:Deoxycytidine Monophosphate; C098393:amdoxovir; D003570:Cytidine Triphosphate; D016047:Zalcitabine; D000068698:Tenofovir; D054303:HIV Reverse Transcriptase; D000068679:Emtricitabine; D000225:Adenine; C099405:dexelvucitabine