Pharmaceutical industry, protease

In apoptosis a series of events takes place in an orderly sequence involving the activation of various proteases which are called caspases, for cysteine and aspartate proteases. Several distinct caspases act in a cascade vaguely reminiscent of the blood-clotting cascade of complement proteins. If one wishes to interfere with the apoptotic process, then one strategy would be to develop drugs that inhibit various caspases, a current effort underway in the pharmaceutical industry. 

Peptide synthesis is an extremely important area of chemistry for the pharmaceutical industry, and like any specialized area of chemistry, has its own set of unique problems associated with it. Racemization and purification of final products are two of the most difficult problems in this area. The use of enzymes has been explored as a possible answer to these problems since 1938 [29]. However, proteases needed to catalyze peptide synthesis are subject to rapid autolysis under the conditions needed to affect peptide coupling, so this has generally not been a practical approach until cross-linked enzyme crystals of proteases became available. The synthetic utility of protease-CLCs was demonstrated by the thermolysin CLC (PeptiCLEC -TR)-catalyzed preparation of the aspartame precursor Z-... 

BACE-1 is a membrane-anchored aspartic acid protease that is localized to the acidic compartments of endosomes and lysosomes in the CNS and has an optimal enzymatic activity at around pH 5. As a consequence, a BACE-1 inhibitor needs to be able to cross the blood-brain barrier and to have a significant non-protein bound fraction in order to reach the active site of the enzyme. This makes traditional aspartic protease inhibitors, which typically are large and peptidic, unsuitable as BACE-1 inhibitors. Moreover, the BACE-1 active site is extended, shallow and hydrophilic (Fig. 2) [99]. Therefore, the development of potent, selective, orally active, and brain penetrant low MW compounds has been a big challenge for the pharmaceutical industry [101, 102],... 

Chemical synthesis remains as important to society as it became during World War II, when the modem pharmaceutical industry originated in its efforts to develop penicillins. Ever since, organic chemists literally have made the drugs that relieve our illnesses. Further examples include the antiinflammatory cortisone, developed in the 1940s to treat arthritis, and the protease inhibitors indinavir, ritonavir, and saquyinavir, introduced in 1995 to suppress the human immunodeficiency virus (HfV). 

Die synthesis of enantiomerically pure inteimediates and active products is a major requiiement for the pharmaceutical industry. Hydrolytic biocatalysts such as esterases, lipases and proteases aie employed for the preparation of enantiopure compounds from racemic precursors, prochiral compounds, and diastereomeric mixtures. Hydrolytic enzymes alsocatalyze reverse hydrolysis and thus offer access to both enantiomers of a specific compound. Examples aie the use of enol esters as trani-esterification reagents and the combination of hydi olytic enzymes with racemization catalysts. 

TEMPO-catalyzed oxidations are replacing more familiar oxidation methods, especially in the pharmaceutical industry. An early step in the synthesis of an HIV protease inhibitor is the oxidation shown where the desired ketone is formed in 98% yield in the presence of 1 mol % of TEMPO. 

Proteases account for the majority of enzyme sales in industry, the main markets being in the cleaning and food industries, with a small proportion in the chemical and pharmaceutical industries. The scope for extremely (thermo)stable proteases in these commercial niches has been commented on in several reviews [e.g. 278]. Because of the denaturing effect of heat, when mesophilic proteins are substrates for proteases from extreme thermophiles very high specific activities can be attained at high temperatures. Temperature coefficients are also high. 

The objective of cloning bacterial protease genes has been mainly the over production of enzymes for various commercial applications in the food, detergent and pharmaceutical industries. The virulence of several bacteria is related to the secretion of several extracellular proteases. Gene cloning in these microbes was studied to understand the basis of their pathogenicity and to develop therapeutics against them. Proteases play an important... 

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