Protease inhibitor enzymes

If St. John s wort can alter levels of cyclosporin in the blood, might it not also interfere with the action of other medications Recent research indicates that it can. Not surprisingly, the affected drugs are those that, like cyclosporin, are also metabolized by cytochrome enzymes. Protease inhibitors, used in the treatment of hiv infections, are a prime example. Because of the popularity of St. John s wort as an antidepressant and the incidence of depression in patients diagnosed with HIV infections, researchers at the U.S. National Institutes of Health decided to investigate the consequences of using the herbal remedy and the protease inhibitor indinavir concurrently. Doctors prescribe indinavir to prevent the hiv virus... 

In food processing, the major objectives are sometimes achieved at the expense of some loss of recognised nutrients. However, in other cases, important nutrients may become available only after appropriate processing, since inhibitors or other interfering compounds may be destroyed or inactivated. Toxic factors can sometimes be destroyed by denaturation, as with enzymes, protease inhibitors and phyto-haemagglutinins. They can also be physically removed, for example by leaching, solvent extraction or solid classification methods, as in the removal of gossypol from cottonseed protein, or of phytate from cereals. 

The most recent advance in treating HIV infections has been to simultaneously attack the virus on a second front using a protease inhibitor. Recall from Section 27.10 that proteases are enzymes that catalyze the hydrolysis of proteins at specific points. When HIV uses a cell s DNA to synthesize its own proteins, the initial product is a long polypeptide that contains several different proteins joined together. To be useful, the individual proteins must be separated from the aggregate by protease-catalyzed hydrolysis of peptide bonds. Protease inhibitors prevent this hydrolysis and, in combination with reverse transcriptase inhibitors, slow the reproduction of HIV. Dramatic reductions in the viral load in HIV-infected patients have been achieved with this approach. 

Protease inhibitor (Section 28.13) A substance that interferes with enzyme-catalyzed hydrolysis of peptide bonds. 

The matrix metalloproteinases are inhibited by specific endogenous tissue inhibitor of metalloproteinases (TIMPs), which comprise a family of four protease inhibitors TIMP-1, TIMP-2, TIMP-3, and TIMP-4. Overall, all MMPs are inhibited by TIMPs once they are activated but the gelatinases (MMP-2 and MMP-9) can form complexes with TIMPs when the enzymes are in the latent form. 

Casado JL, Perez-Ehas MJ, Marti-Belda P, Antela A, Suarez M, Ciancas E et al. (1998) Improved outcome of cytomegalovirus retinitis in AIDS patients after introduction of protease inhibitors. J Acquir Immune Defic Syndr Hum Retrovirol 19 130-134 Catalano CE (2000) The terminase enzyme from bacteriophage lambda a DNA-packaging machine, Cell Mol Life Sci 57 128-148... 

Reverse transcriptase inhibitors prevent DNA from being produced in newly infected cells. They do not, however, prevent the reactivation of HIV from previously infected cells, the reason being that the enzyme is not involved in this process. Thus, agents that act at a later point in the replication cycle, possibly preventing reactivation, would be a major advance in the treatment of AIDs sufferers. The HIV protease inhibitors, which are currently receiving considerable attention, are believed to act in the manner depicted in Fig. 5.24. 

In addition to proteases, other inhibitors reduce the activity of amylase and other digestive enzymes (Ishimoto et al, 1999). Many varieties of beans produce a glycoprotein that complexes with and inhibits a-amylase (Mirkov et al, 1995). The amylase inhibitors are non-competitive and thermostable (Gallaher and Schneeman, 1986) and, unlike protease inhibitors, do not elicit heightened secretion of amylase (Toskes, 1986). Although over-expression... 

Pancreatic secretion for many, if not most, species is regulated in order to insure adequate protein digestion. Correspondingly, protease inhibitors have a greater impact on pancreatic secretion than do inhibitors of amylase and lipase (Toskes, 1986). The secretory response of the exocrine pancreas to protease inhibitors can be rapid (< 10 min), does not involve parallel increases in the secretion of all enzymes (Holm et al., 1992), and is probably mediated by a signaling pathway (see below). 

There is evidence that protease inhibitors selectively regulate the activity of specific digestive enzymes at the level of gene expression (Rosewicz et al., 1989). Specifically, soybean trypsin inhibitor increases secretion of proteases, including a form of trypsin that is resistant to inhibition but does not cause an increase in amylase secretion. Although the relationships between protease inhibitors and exocrine pancreatic secretion have received the most attention, pancreatic secretion is increased when potato fiber is added to the diet (Jacob et al., 2000), although the mechanism and signaling pathway have not been elucidated. 

Plasminogen activator inhibitors have been shown to be present in a large variety of different cells and tissues. These inhibitors are thought to play an important role in regulating tissue fibrinolysis. One of these inhibitors has been purified from cultured bovine aortic epithelial cells. This inhibitor has been shown to be a serine protease inhibitor and inhibits the function of two proteolytic enzymes urokinase and tissue plasminogen activator, both of which cleave and activate plasminogen. The mechanism by which this inhibitor functions is very similar to that described above with a-l-PI. Thus, the inhibitor forms a binary complex with the proteolytic enzyme and thereby inhibits its activity. Again in a situation comparable to that with a-l-PI, it was found that when the purified bovine aortic epithelial inhibitor was exposed to Al-chlorosuccinimide,... 

The HlV-1 protease is responsible for processing the protein precursors to the enzymes (integrase, protease and reverse transcriptase) and the structural proteins of the HIV-1 virus. Maw and Hall found that topological indices provide rehable QSAR models for the IC50 data of 32 HIV-1 protease inhibitors [29]. The best QSAR model, with r = 0.86, s=0.60 and q = 0.79, was obtained with the shape index Ka, the connechvity index the sum of HE-state indices for ah groups that act as... 

Protease inhibitor A drug that acts by inhibiting the viral protease enzyme, which prevents long strands of protein from being cleaved into the smaller proteins the virus requires for assembly. 

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