ABSTRACT
Dolutegravir is a human immunodeficiency virus (HIV) integrase strand–transfer inhibitor (INSTI), consisting of a chiral nonracemic tricyclic carbamoyl pyridone–containing heterocycle core and a benzyl carboxamide moiety. Dolutegravir was discovered using a pharmacophore-based design approach to construct a bioisostere of the integrase phosphodiester substrate. As such, dolutegravir was designed to bind two divalent magnesium ions within the integrase catalytic active site, which effectively prevents the productive integration of viral and host deoxyribonucleic acid (DNA) substrates through inhibition of the second biochemical step catalyzed by HIV integrase known as strand transfer. Dolutegravir has no appreciable inhibition of the first biochemical step catalyzed by integrase known as 3’ processing, which is consistent with the two-metal binding mechanism of action (Johns et al., 2013). Dolutegravir is a specific inhibitor of HIV-1 and HIV-2 and has some antiviral activity against select non-HIV viruses, as described in section 2a, Routine susceptibility.
