Nucleoside kinase transcriptase inhibitors

Didanosine is a synthetic purine nucleoside analog that inhibits the activity of reverse transcriptase in HIV-1, HIV-2, other retroviruses and zidovudine-resistant strains. A nucleobase carrier helps transport it into the cell where it needs to be phosphorylated by 5 -nucleoiidase and inosine 5 -monophosphate phosphotransferase to didanosine S -monophosphate. Adenylosuccinate synthetase and adenylosuccinate lyase then convert didanosine 5 -monophosphate to dideoxyadenosine S -monophosphate, followed by its conversion to diphosphate by adenylate kinase and phosphoribosyl pyrophosphate synthetase, which is then phosphorylated by creatine kinase and phosphoribosyl pyrophosphate synthetase to dideoxyadenosine S -triphosphate, the active reverse transcriptase inhibitor. Dideoxyadenosine triphosphate inhibits the activity of HIV reverse transcriptase by competing with the natural substrate, deoxyadenosine triphosphate, and its incorporation into viral DNA causes termination of viral DNA chain elongation. It is 10-100-fold less potent than zidovudine in its antiviral activity, but is more active than zidovudine in nondividing and quiescent cells. At clinically relevant doses, it is not toxic to hematopoietic precursor cells or lymphocytes, and the resistance to the drug results from site-directed mutagenesis at codons 65 and 74 of viral reverse transcriptase. 

Tenofovir is a nucleotide (nucleoside monophosphate) analogue reverse transcriptase inhibitor, given as a prodrug, tenofovir disoproxU fumarate. In contrast to the other members of this class, it only needs to be phosphorylated twice intraceUularly before it is pharmacologically active. Adverse effects have been reported as flatulence, raised transaminases, raised creatine kinase activity, and rarely a raised serum creatinine (1). Tenofovir does not currently appear to be nephrotoxic. 

The NRTIs are nucleoside analogues that act as competitive inhibitors of reverse transcriptase. After conversion to the triphosphate form by host cell kinases, these drugs compete with nucleoside triphosphates for access to reverse transcriptase. All NRTIs lack a 3 -hydroxyl group thus, their incorporation into a growing DNA chain results in its termination. These drugs block HIV replication and therefore the infection of new cells, but they have little effect on cells already infected with virus. Combination therapies often include two NRTIs that are analogues of different bases plus a protease inhibitor. The pharmacokinetic properties of the NRTIs are listed in Table 51.2. 

Although the 5 -triphosphate of ddU is a potent inhibitor of reverse transcriptase, the parent nucleoside is inactive because it is a poor substrate for thymidine kinase. In an attempt to by-pass this phosphorylation step, the bis(pivaloyloxymethyl) triester of ddU 5 -monophosphate (44, Nu = 5 -ddU) was prepared [59]. This membrane-permeable prodrug is active against HIV-1 in either MT-4 or thymidine kinase-deficient CEM cells, and it has been shown to release the 5 -monophosphate of ddU in both cell lines. 

---