Tenofovir alafenamide is a novel tenofovir prodrug nucleoside analog reverse transcriptase inhibitor developed in order to improve renal safety when compared to the counterpart tenofovir disoproxil. It is used for the treatment of chronic hepatitis B virus infection in adults with compensated liver disease. Both of these prodrugs were first created to cover the polar phosphonic acid group on tenofovir by using a novel oxycarbonyloxymethyl linkers to improve the oral bioavailability and intestinal diffusion. In the liver, tenofovir alafenamide is converted into tenofovir alanine by the enzymes Lysosomal protective protein and Liver carboxylesterase 1.Tenofovir alanine is then converted to Tenofovir by the enzyme Histidine triad nucleotide-binding protein 1. It is then transported into the blood via multidrug resistance-associated protein 4 or Solute carrier family 22 then into the infected cell via the same or similar transporters. Tenofovir is then converted to the active metabolite, tenofovir diphosphate, a chain terminator, by constitutively expressed enzymes in the cell. Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and the Hepatitis B polymerase by direct binding in competition with dATP. After integration into DNA, causes viral DNA chain termination. Tenofovir diphosphate lacks the 3'-OH group which is needed to form the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation, therefore, once tenofovir diphosphate gets incorporated into DNA, this causes DNA chain termination, preventing the growth of viral DNA. Less viral proteins are therefore produced, and there is a reduction in new viruses being formed.

Tenofovir Alafenamide Pathway References