Reverse Transcriptase Inhibitors

HIV RT is a multifunctional enzyme with RNA-dependent DNA polymerase, ribonuclease (RNase) H, and DNA-dependent DNA polymerase activities. The active protein is a heterodimer comprising p66 and p51 subunits. The N-terminal 440 amino acids of p66 contain polymerase activity and the C-terminal 120 residues show RNase H domain. The p51 of the subunit of HIV-RT corresponds to the polymerase domain of the p66 subunit. The crystal structure of RT has been resolved and identifies four individual subdomains: fingers, palm, thumb and connecting region. The overall folding of p66 and p51 is similar, but the spatial arrangements of the two subdomains are extremely different. Highly conserved regions located in the p66 region, together with two alpha helices of the thumb act as a clamp to position the template-primer relative to the polymerase active site, which is located in the palm region. The 3' end of the primer terminus is close to residues AspllO, Aspl85 and Aspl86 in the catalytic site. A spatially distinct hydrophobic pocket comprising residues Tyrl81 and Tyrl88 in p66 form crucial components for binding non-nucleoside RT inhibitors. Inhibitors of RT can be divided into two categories. The first group include the nucleoside analogues (NRTI) such as zidovudine (ZDV, 3'-azido-2'3'-dideoxythymidine), didanosine (ddl, 2'3'-dideoxyinosine) and zalcitabine (ddC, 2'3'-dideoxycytidine), which compete with normal 2'-deoxynucleoside triphosphates (dNTP) precursors of DNA, whereas the second group comprise structurally diverse compounds referred to as non-nucleoside reverse transcriptase inhibitors (NNRTI). The chemical structures of some of the commonly used reverse transcriptase inhibitors are shown in Fig. 1.

Nucleoside inhibitors (NRTI)

Zidovudine (ZDV); didanosine (ddl); lamivudine (3TC, (—)-2'-deoxy-3'-thiacytidine), stavudine (d4T, 2' 3 '-dideoxythymidine) and zalcitabine (ddC) are currently licensed drugs but their efficacy has been limited owing to both pharmacological factors and emergence of resistant virus strains. Several newer compounds have greatly improved pharmacological properties. Some examples include: N6-cyclopropylamino 2'3'-dideoxyguanosine (abacavir, BW1592U89), the acyclic phosphonate analogues 9- (2-phosphonylmethoxyethyl) adenine (adefovir, PMEA) and its propyl counterpart, PMPA (9-(2-phosphonylmethoxypropyl)adenine, and F-ddA (2'-^-fluoro-2'3' -dideoxyadenosine). All these com-

Nucleoside HT inhibitors (NHTI) O

CH s

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