Protease, inhibition

The concept of a proteolytic mechanism in the production of inflammatory manifestations is supported by the demonstration of anti-inflammatory activity in various protease inhibitors, e.g. the trypsin inhibitors of the pancreas, soya bean, ovomucoid and potato . It is interesting to note that the inhibitor from potatoes exerts its effect even after the inflammation is well established , suggesting that protease action is a continuing feature of inflammation and not simply an initiating process. Various esterase inhibitors (dyflos, quinine, quinidine and chloroquine) also reduce capillary permeability induced by heat and the permeability globulins . 

Damgaard and Weinstein have shown that certain well recognized anti-inflammatory drugs, salicylic acid, phenazone, amidopyrine, cinchophen and also jf)-aminophenol inhibit fibrinolysin (plasmin) in concentrations close to those which show anti-inflammatory activity in vivo. Salicylate may inhibit kinin formation by this indirect mechanism involving plasmin. The failure of some workers to observe any inhibition of kallikrein by salicylate in vitro does not conflict with this. 

Lack and Ali have reported that the tissue activator of plasminogen resides in the lysosomal fraction of cell cytoplasm and is inhibited by amino-caproic acid. This is noteworthy, since other workers have postulated that the anti-inflammatory activity of cortisone may be attributable to its ability to prevent the release of lysosomal proteases by stabilizing the lysosomal membrane. Chloroquine may act similarly . 

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Grtitter, M.G., et al. Crystal structure of the thrombin-hirudin complex a novel mode of serine protease inhibition. EMBO J. 9 2361-2365, 1990. 

Shimba N, Nomura AM, Mamett AB, Craik CS (2004) Herpesvirus protease inhibition by dimer disruption. J Virol 78 6657-6665... 

Table 6.6 Some of the most commonly employed protease inhibitions and the specific classes of proteases they inhibit...

M. Clare, R. A. Mueller, and K. Houseman, Effect of hydroxyl group configuration in hydroxyethlamine dipeptide isosteres on HIV protease inhibition, J. Med. Chem. 34 1222(1991). 

A series of phenethylamide-based NS3 inhibitors was disclosed [127] and subsequently elaborated to yield more potent analogs, such as 66 (Kj = 100 nM) [128], Similarly, a second series of phenethylamide [129] and sulfonamide-containing serine traps, exemplified by 67 were prepared and exhibit potent (20-60 nM) protease inhibition, although no cell-based data is given [130],... 

The work that paved the way toward enzymatic inhibition was published in the early 1990s by Wudl and coworkers (Schinazietal., 1993 Friedmanetal., 1993 Sijbesma et al., 1993) and since then studies regarding antiviral activity, mainly HIV-protease inhibition, have been carried out to find active compounds. Up to now, the most effective fullerene derivatives are the trans-2, -dimethy 1-bis-fulleropyrrolidin-ium salt (Fig. 1.4) (Marchesan et al., 2005) and the dendrofullerene reported by Hirsch (Schuster et al., 2000) both of them present an ECJ0 of 0.2pM. Also HIV reverse transcriptase can be inhibited by, -dimcthyl-bis-fulleropyrrolidinium salts (Mashino et al., 2005). The same compounds are also active against acetylcholine esterase (AChE), an enzyme that hydrolyzes a very important neurotransmitter. 

Nakamura E, Tokuyama H, Yamago S, Shiraki T, Sugiura Y (1996) Biological activity of water-Soluble fullerenes. Structural dependence of DNA cleavage, cytotoxicity, and enzyme inhibitory activities including HIV-Protease inhibition. Bull. Chem. Soc. Jpn. 69 2143-2151. 

Protease Inhibition and Antioxidant Aetions of Some Aqueous Allium Extraets... 

The experiment with 0.5 g/mL of erode extracts of different parts of Allium plants (bulb, green leaf, white stalk) showed the inhibition of acrosin and trypsin activities, mostiy the red onion and garlic extracts. These results demonstrated that spermicidal effect of Allium extracts is determined also by their capacity of protease inhibition. The red onion extract shows the higher antioxidant capacity and a very low cytotoxicity. 

Keywords Allium extracts, antioxidant capacity, cytotoxicity, garlic, protease inhibition... 

OrganosuUur compounds have been shown to modulate the activity of glutathione -transferases (GST), a family of enzymes important in detoxification of carcinogens [24], and cytochromes P450 (CYP), a family of enzymes that activate many chemical carcinogens in experimental animals [25]. The effect of proteases inhibition is a new aspect of the biological activity of these plants and further research should be carried out to identify the specific compounds from Allium or Allium products that are responsible for this biochemical effect. 

Today, about eight new protease-inhibiting drugs have been approved for use by the FDA. All act by bonding in some way or another... 

Inhibition of trypsin and other proteases Inhibition of chymotrypsin Transport of lipids... 

Pharmacology Ritonavir is an inhibitor of the HIV-1 and HIV-2 proteases. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to production of noninfectious immature HIV particles. 

Pharmacology Nelfinavir is an inhibitor of the HIV-1 protease. Inhibition of the viral protease prevents cleavage of the gagpol polyprotein resulting in the production of immature, noninfectious virus. 

Protease inhibition. Water extract of the dried twig of Olea europaea ssp. africam, was inactive on Bacteroides intermedius, IC50100 p,g/mL and Treponema denticola, IC50 greater than 250 p-g/mL, and active on Bacteroides gingivalis, IC50 75 pg/mL . 

Inhibition of Aspartyl Proteases Inhibition of aspartyl proteases has... 

Inhibitors of proteases have also been developed from polymers. These molecules are as simple as a polymer chain, or much more complex. The mechanisms for protease inhibition are variable depending upon the type of molecule used specific protease inhibitors are available for conjugation to a polymer while other polymeric inhibitors inhibit all divalent cation dependent proteases. The development of these inhibitory polymers and polymer conjugates greatly increase the possibility to protect proteins from degradation in the gastrointestinal tract. 

Lee, T. G. and Maruyama, S. (1998). Isolation of HTV-1 protease-inhibiting peptides from thermolysin hydrolysate of oyster proteins. Biochem. Biophys. Res. Commun. 253, 604-608. 

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