There are two types of anti-RT drugs: nucleoside analog RT inhibitors (NRTIs) and nonnucleoside inhibitors (NNRTIs). NRTIs are, as the name implies, analogs of the normal nucleosides RT uses to synthesize viral DNA. The nucleoside analogs used as NRTIs lack a normal 3'OH, and, as a consequence, act as chain terminators when incorporated into viral DNA. Unfortunately, NRTIs can also be incorporated into host DNA; if they are incorporated, and not removed by host cell repair enzymes, NRTIs can block the replication of host cells. As a consequence there are problems with the toxicity of NRTIs.
In addition, there are problems with the development of viral resistance. Resistance to an NRTI implies that the resistant virus is better able to discriminate against the NRTI. NRTI resistance mutations are in RT; resistant RTs must retain the ability to incorporate normal dNTPs, but must either be able to block the incorporation of NRTIs, or selectively excise NRTIs after they have been incorporated. NRTI-resistant RTs make use of both mechanisms. 3TC-resistant RTs incorporate 3TCTP much less well than wild-type RT (see Figure 2); AZT-resistant RTs selectively excise AZTMP after it has been incorporated (see Figure 6).
|
