Islatravir

The molecular mechanism of islatravir is unique among antiretrovirals, as it functions as a nucleoside reverse transcriptase translocation inhibitor (NRTTI). Unlike traditional NRTIs that only act via chain termination, islatravir exerts a dual-action inhibitory effect on the HIV-1 reverse transcriptase (RT) enzyme.

Upon entering the host cell, islatravir is phosphorylated by cellular kinases, primarily deoxycytidine kinase (dCK), into the pharmacologically active islatravir-triphosphate (ISL-TP). ISL-TP is incorporated into the nascent viral DNA chain by RT. The 4'-ethynyl group acts as a "molecular wedge" that prevents the translocation of the RT enzyme to the next nucleotide position, immediately halting further DNA elongation. If the enzyme manages to translocate past the initial block, the structural changes induced by the 4'-ethynyl group in the DNA-RT complex prevent the incorporation of the subsequent nucleotide, effectively terminating the chain shortly thereafter. Islatravir-triphosphate demonstrates high selectivity for viral RT over human cellular DNA polymerases beta and gamma, though it shows weak inhibition of human DNA polymerase alpha at very high concentrations.