Lopinavir Ritonavir Kaletra

Ball-and-Stick Model Space-filling Model

Structural Formula

Structural Formula

; Oxygen

= Carbon

= Hydrogen

; Oxygen

= Nitrogen

Year of discovery: Early 1990s (Abbott Laboratories); Year of introduction: 2000 (only in combination with ritonavir as Kaletra); Drug category: HIV protease inhibitor; Main uses: For the treatment of HIV-infection in combination with other antiretroviral agents; Related drugs: Ritonavir (Norvir), Indinavir (Crixivan), Saquinavir (Fortovase & Invirase), Nelfinavir (Viracept), Fosamprenavir (Lexiva).

The anti-HIV drug Kaletra is a combination of two HIV protease inhibitors, lopinavir and ritonavir. The enzyme HIV protease plays an important role in the late phase of the viral life cycle, in which the large proteins Gag and Gag-Pol are cleaved to generate smaller structural proteins that associate to form the body of the virus. Cleavage of Gag-Pol also leads to essential viral enzymes, such as reverse transcriptase, protease and integrase. HIV protease must cleave Gag and Gag-Pol at specific peptide bonds to generate functional viral proteins. These proteins are required for the assembly of the new viral particles. Without them, the newly formed viruses cannot mature or become infectious. For this reason, targeting the enzyme HIV protease with specific inhibitors has been the focus of much research since the early 1990s.1

Aspartic acids (in the protease active site)

Gag-Pol Substrate

Aspartic acids (in the protease active site)

- vnYjW

Transition-state intermediate ho oh h if v

- vnYjW

Transition-state intermediate

The enzyme HIV protease contains two aspartic acid residues in the active site that play a crucial role in enzymatic activity (see above). Specifically, one of the peptide bonds of the substrate (gray box) is attacked by an enzyme activated molecule of water (blue) to form a metastable (transient) intermediate (yellow box), which then undergoes spontaneous peptide bond cleavage to afford acid and amine products. The three-dimensional structure of HIV protease was first determined in

1989 by A. Wlodawer at NIH.2 This finding greatly facilitated the rational design of competitive HIV protease inhibitors. The early inhibitors were transition-state mimics which had strong affinity for the enzyme and were stable to it (see yellow boxes). The first FDA approved HIV protease inhibitor, saquinavir (Invirase™, Roche), was soon followed by ritonavir (Norvir™, Abbott). Abbott later developed a more potent protease inhibitor, lopinavir, which was found to be even more effective when co-formulated with ritonavir. Ritonavir inhibits the liver enzyme cytochrome P450-3A4 that rapidly metabolizes lopinavir. As a result, when used in combination with ritonavir, lopinavir has an extended half-life and is effective at lower doses. The X-ray crystal structure of lopinavir (red) bound to HIV-1 protease is shown below.''

yZN CHj UN

sV«AsV

yZN CHj UN

Ritonavir (Norvir'"")

Ritonavir (Norvir'"")

1. Drug Dev. Res. 2006, 67, 501-510; 2. Science 1989, 245, 616-621; 3. Bioorg. Med. Chem. 2002, 10, 2803-2806. (1MUI); Refs. p. 178

Saquinavir (Invirase™)

Aspartic Acid

Lopinavir

1. Drug Dev. Res. 2006, 67, 501-510; 2. Science 1989, 245, 616-621; 3. Bioorg. Med. Chem. 2002, 10, 2803-2806. (1MUI); Refs. p. 178

Aspartic Acid

Lopinavir

0 0

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