Efavirenz Sustiva

Structural Formula Ball-and-Stick Model Space-filling Model

= Carbon = Hydrogen ^ = Oxygen ^^ = Nitrogen = Fluorine = Chlorine

Year of discovery: Early 1990s (DuPont Merck now Bristol-Myers Squibb); Year of introduction: 1998 (Bristol-Myers Squibb/Merck); Drug category: Non-nucleoside reverse transcriptase inhibitor; Main uses: For the treatment of HIV-1 infections in adults and children as a fixed dose combination therapy (Atripla); Related drugs: Nevirapine (Viramune), Delavirdine (Rescriptor).

Efavlrenz is a potent second-generation HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI). The viral enzyme reverse transcriptase (RT) is responsible for copying single-stranded viral RNA into the double-stranded DNA that is required for the replication of HIV. This RT operates with a high error rate which, when coupled with the rapid rate of HIV replication, leads to high rates of genetic mutation and the rapid appearance of drug resistant strains by natural selection over drug-susceptible strains. These mutant HIV strains are often resistant to other classes of antiretroviral drugs as well, severely limiting treatment options. The first-generation NNRTIs such as nevirapine and delavirdine also produce resistant strains - suffering, for instance, a 100-fold loss in binding affinity to HIV-1 RT as a result of the mutation of a single amino acid residue (Tyr181 to Cys181) in the active site of the viral enzyme.

The rapid emergence of resistant HIV-1 strains spurred the development of second-generation NNRTIs that are more potent and somewhat less sensitive to single point mutations. Efavirenz was discovered in the early 1990s, and in 1998 it was introduced as Sustiva™ by BMS and Merck (as Stocrin™ in Europe). It is now used in combination with other classes of antiretroviral drugs, for example, with lamivudine and tenofovir (or zidovudine) to suppress HIV replication in individuals who have not previously been treated. Efavirenz is also useful for patients who already failed one or two classes of antiretroviral drugs. Efavirenz was shown to be well-tolerated even after long-term treatment (10 months or more). Recently, a new formulation combining fixed doses of efavirenz, emtricitabine and tenofovir was approved. It is now available under the trade name of Atripla™ (Gilead Science and BMS).1 The potency of efavirenz allows once-a-day dosing, which increases patient compliance and reduces the probability of the emergence of resistant strains. Atripla is the first multi-class antiretroviral drug formulated in a single pill.

The effect of mutations at the NNRTI-binding pocket of the enzyme reverse transcriptase has been extensively studied. The X-ray crystal structures of the wild-type RT and mutated RT, with and without efavirenz, have been elucidated.2 Efavirenz does not bind to Tyr181 and Tyr188, in contrast to nevirapine, and therefore the nevirapine-induced mutations to Cys181 or Cys188 do not impact the binding of efavirenz to the enzyme. In fact, two other mutations (Lys103 to Arg and Leu100 to lie) must occur simultaneously in order to produce high levels of resistance towards efavirenz, (Lys103 is cyan whereas Leu100 is magenta.)

1. Drugs 2006, 66, 1501-1512, 2. Structure (London) 2000, 8, 1089-1094. ( Fl :.j; R ifi p. 177
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