Nevirapine Viramune

Ball-and-Stick Model

Space-filling Model

Carbon = Hydrogen S = Oxygen M = Nitrogen

Carbon = Hydrogen S = Oxygen M = Nitrogen

Year of discovery: Early 1990s (Rega Institute for Medical Research); Year of introduction: 1996 (Boehringer Ingelheim); Drug category: Non-nucleoside HIV reverse transcriptase inhibitor; Main uses: For the treatment of HIV infections as part of combination therapy with zidovudine and didanosine; Also as a single-dose therapy in HIV-infected pregnant women to prevent mother-to-child transmission of the virus; Related drugs: Delavirdine (Rescriptor), Efavirenz (Sustiva).

Nevirapine is an anti-HIV drug that blocks the HIV enzyme reverse transcriptase and thereby prevents viral replication.1 It was discovered in Belgium in the early 1990s ana currently is a first-line treatment for HIV-1 infection in combination with other antiretroviral drugs such as HIV protease inhibitors and nucleoside reverse transcript-tase inhibitors. These drugs are synergistic, since they act by different molecular mechanisms. Nevirapine is also used to prevent mother-to-child transmission of HIV. Nevirapine does not cure HIV, since it only inhibits the replication of the virus. However, even after the administration of a few doses, a large drop in the levels of circulating HIV is usually observed.

Nevirapine inhibits the enzyme HIV-1 reverse transcriptase (RT), but not the enzyme HIV-2 RT. Unlike nucleoside RT inhibitors such as zidovudine and zalcitabine, nevirapine does not bind at the active site of the enzyme, but instead, at a non-substrate binding site, referred to as the allosteric non-nucleoside reverse transcriptase inhibitor (NNRTI)-binding pocket. The NNRTI-binding pocket is located only 10 A below the substrate-binding site of the enzyme. The binding of nevirapine results in a change of the catalytically active conformation of the enzyme into a fixed inactive conformation. Locked in this inactive conformation, the enzyme cannot copy the single-stranded viral RNA to cDNA, the intermediate leading to genomic double-stranded DNA. The figures below show ligand-free HIV-1 RT and also the same enzyme complexed with cDNA. (The template viral RNA strand is shown in cyan;

see also scheme on page 152). The structure of HIV-1 RT with nevirapine (shown as red spheres) occupying the NNRTI-binding pocket (transparent mesh representation) is shown in the bottom panel. Part of the tricyclic core of nevirapine binds in a face-to-face attraction with the flat rings of tyrosines 181 and 188.2 A single mutation of Tyr181 to Cys181 results in the loss of significant binding energy and a 100-fold lower binding affinity.3 This and the high error rate of RT explain why resistance can develop rapidly - even after a few doses of nevirapine monotherapy.

NNRTI-binding Pocket

Ligand-free HIV-1 Reverse Transcriptase

Nevirapine cDNA Bound to HIV-1 Reverse Transcriptase

Nevirapine in HIV-1 Reverse Transcriptase (1VRT)

cDNA Bound to HIV-1 Reverse Transcriptase

1. Int. J. Clin. Pract. 2006, 61, 105-118; 2. Nat. Struct. Biol. 1995. 2, 293-302. (1 VRT); 3. J. Mol. Biol. 2001, 312, 795805 (1JLB); Refs. p. 177

Active Site (Substrate-binding Site)

Ligand-free HIV-1 Reverse Transcriptase

Active Site (Substrate-binding Site)

NNRTI-binding Pocket

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