HIV (human immunodeficiency virus) is a virus that attacks the body’s immune system. HIV infection in humans came from a type of chimpanzee in Central Africa. Studies show that HIV may have jumped from chimpanzees to humans as far back as the late 1800s. Over decades, HIV slowly spread across Africa and later into other parts of the world. The virus has existed in the United States since at least the mid to late 1970s. Infection with HIV occurs by the transfer of blood, semen, vaginal fluid, pre-ejaculate, or breast milk. HIV infects vital cells in the human immune system such as helper T cells, macrophages, and dendritic cells. HIV infection leads to low levels of CD4⁺ T cells through a number of mechanisms, including apoptosis of uninfected bystander cells, direct viral killing of infected cells, and killing of infected CD4⁺ T cells by CD8 cytotoxic lymphocytes that recognize infected cells. When CD4⁺ T cell numbers decline below a critical level, cell-mediated immunity is lost, and the body becomes progressively more susceptible to opportunistic infections.

HIV integrase is a multidomain enzyme which is required for the integration of viral DNA into the host genome. It is an attractive target for therapeutic drug design. It is one of three enzymes of HIV, the others being the Reverse Transcriptase and the Protease. HIV integrase catalyzes the insertion into the genome of the infected human cell of viral DNA produced by the retrotranscription process. HIV integrase includes HIV-1 and HIV-2 integrases. HIV-1 integrase is a 32-kDa enzyme that carries out DNA integration in a two-step reaction.

Dolutegravir is a potent and orally active HIV-1 integrase inhibitor

Dolutegravir (S/GSK1349572) is the first next-generation integrase strand transfer inhibitor. Therefore， Dolutegravir ptently inhibits wild-type HIV-1 viral replication. Meanwhile, Dolutegravir retains a high potency against the HIV-1 Y143R, N155H, and G140S/Q148H mutants. What’s more, Following a single intravenous (IV) administration of Dolutegravir, the plasma clearance is low in rats and monkeys. The half-lives in the rat and monkey are similar, approximately 6 h, and the steady-state volume of distribution is low. Following oral administration, Dolutegravir is rapidly absorbed with a high oral bioavailability when administered as a solution to fasted male rats and a single monkey.

All in all, Dolutegravir is a highly potent and orally active HIV-1 integrase inhibitor that is effective in HIV-1 infection.

References:

[1] Chiu TK, et, al. Curr Top Med Chem. 2004;4(9):965-77.

[2] Fantauzzi A, et, al. Ther Adv Chronic Dis. 2014 Jul;5(4):164-77.