NIAID HIV/OI Searchable Chemical Database

Protease Inhibitors

Saquinavir (green) bound to HIV-1 Protease

Protease inhibitors used in combination with reverse transcriptase (RT) inhibitors represent the most effective anti-HIV therapies developed to date. Several studies have reported that combination therapies reduce HIV viral load to undetectable levels for sustained periods of time in up to 90% of patients. The use of RT inhibitors not only results in synergism but also substantially reduces the likelihood of protease or multiple-resistant HIV strains developing. Monotherapy, especially low dose therapy, often results in the rapid emergence of protease resistant HIV strains. Resistance has been mapped to several key amino acid residues and cross-resistance among the protease inhibitors has been observed. Most current protease inhibitors are complex peptidomimetic compounds with poor aqueous solubility, low bioavailability and short plasma half-lifes. The complexity of these agents not only contributes to their high cost but also increases the potential for unwanted drug interactions.

The development of protease inhibitors has been facilitated by the determination of a three dimensional structure of the HIV protease, extensive knowledge gained from other aspartyl proteases and their inhibitors, such as renin, and the identification of the HIV protease cleavage sites (Tyr | Pro, Phe | Pro, Leu | Ala, Met | Met, Phe | Tyr, Phe | Leu, and Leu | Phe). All of the HIV protease inhibitors that have been approved and most that are in development, are non-hydrolysable transition state peptidomimetics in which the cleavage site peptide linkage is replaced is replaced by transition state isosteres, such as statine, norstatine, hydroxyethylene, a reduced amide, hydroxyethyl, or dihydroxyethylene. Many inhibitors have been designed to be symmetrical to take advantage of the C2 symmetry of the dimeric enzyme. Although symmetrical inhibitors can result in tighter binding as well as a simpler design and synthetic pathway, symmetrical compounds may be more susceptible to viral resistance since single mutations in the protease have multiplicative effects on inhibitor binding.

Rational iterative drug design based on structural studies of the HIV protease in conjunction with molecular modeling has yielded many compounds in a brief period of time with significant clinical potential. Four protease inhibitors, saquivanir (Invirase®, Hoffman-LaRoche), ritonavir (Norvir®, Abbott), indinavir (Crixivan®, Merck) and nelfinavir (Viracept®, Agouron) have already been approved and several others are in the late stages of clinical development. Current efforts are underway to develop simpler compounds with higher bioavailability and less susceptibility to viral resistance. Pharmacokinetic problems are also being addressed through the development of prodrugs, the improvement of formulations and the development of inhibitors of liver metabolizing enzymes.

Approved Protease Inhibitors

• Saquinavir
• Ritonavir
• Indinavir
• Nelfinavir
• Amprenavir

References

1. WLODAWER A.; VONDRASEK J. INHIBITORS OF HIV-1 PROTEASE: A MAJOR SUCCESS OF STRUCTURE-ASSISTED DRUG DESIGN. ANNU REV BIOPH BIOM 27: 249-284 (1998).
2. FLEXNER C., HIV-PROTEASE INHIBITORS. NEW ENGL J MED 338(18): 1281-1292 (1998).