NRTI Mechanism of Action Sample Clauses

NRTI Mechanism of Action. The understanding of viral replication has led to the identification of many therapeutic targets. The conversion of viral RNA into double-stranded viral DNA is catalyzed by HIV RT and is a major target for drug design. HIV RT has been successfully targeted by two drug classes which inhibit its polymerization activity. NNRTIs inhibit HIV RT by binding to an allosteric site on the enzyme that only exists in the presence of an NNRTI.42 The binding of a NNRTI to the allosteric site inhibits the polymerase domain from closing and allowing polymerization to occur.42 NRTIs target the polymerase active site and act as DNA chain terminators, thus inhibiting transcription.42 NRTIs are analogues of naturally occurring nucleic acids that lack a 3’-OH group.42 NRTIs are prodrugs and must be converted to an active metabolite before they are able to inhibit viral transcription.42 All NRTIs, except for tenofovir, are converted to their corresponding triphosphate form by cellular kinases, as exemplified by AZT (Figure 27). Tenofovir is a monophosphonate prodrug and must be converted to its corresponding diphosphate by cellular kinases. The 5’-OH group of the NRTI is converted by cellular kinases to its corresponding triphosphate in three distinct phosphorylation steps. The first step is catalyzed by thymidine kinase (Thd kinase), the second step is catalyzed by thymidylate kinase (TMP kinase), and the third step is catalyzed by nucleoside diphosphate kinase (NDP kinase).
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