Enzyme as therapeutic agents

Enzymes have found a few applications as therapeutic agents. Some examples are transfusion of fresh blood or its active components in bleeding disorders, oral administration of digestive enzymes in digestive diseases 

Acridinium ester used as a chemiluminescent tracer. Labeled acridinium ester in the presence of alkaline hydrogen peroxide undergoes chemical changes producing light that is detected at 430 nm by a photomultiplier detector. 

Competitive binding chemiluminescence assay. The chemiluminescent competitve binding assay is similar to a RIA. The acridinium ester-labeled substance and the endogenous substance compete with the specific antibody that is available in limited concentration. The concentration is determined by the quantity of tracer that binds to the antibody. The use of solid-phase antibody simplifies separation of free from bound tracer. 

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Riley DP (1999) Functional mimics of superoxide dismutase enzymes as therapeutic agents. Chem. Rev. 99 2573-2587. 

Many of these enzyme inhibitors are important as therapeutic agents. Enzyme inhibitors serve as antibiotics, lower our plasma cholesterol and blood pressure, relieve pain and inflammation, help heal our ulcers, reduce our fevers, and treat cancer, among many other uses. Many examples of the therapeutic uses of enzyme inhibitors follow in later chapters. 

Although most of the enzyme-based drugs are inhibitors of enzymes, a number of enzyme preparations have also been developed as drugs for the treatment of a number of diseases. The development of enzymes as therapeutics has been made easier due to the advances in biotechnology. Most successful example of enzyme therapy includes various preparations of plasminogen activators (thrombolytic or fibrinolytic agents) such as a bacterial protein streptokinase and two plasminogen activators... 

The catalytic efficiency and exquisite specificity of enzymes have been exploited for use as therapeutic agents in certain diseases. 

The potential utility of peptides as therapeutic agents with clinical applications is limited as a consequence of intrinsic peptide properties such as metabolic instability or poor transmembrane mobility. Hence, the design and synthesis of meta-bolically stable peptide analogs that can either mimic or block the bioactivity of natural peptides or enzymes is an important area of medicinal chemistry research. Numerous structural modifications to peptides have been examined in pursuit of molecules with more desirable properties [1-3]. These modified structures, peptidomimetics, are nonpeptide molecules that imitate the desired properties of the natural substances. 

Frequently however, enzymes found in the fermentation broth at the time of harvesting are quite different from the state in which they can be used as industrial biocatalysts, reagents in clinical chemistry or as therapeutic agents, The recovery of an enzyme from microbial culture, its concentration and purification will require careful and effective sequential operations, which ate called downstream processing (Wheelwright, 1989). 

The availability of endogenous enzymes and their variants has allowed the use of enzymes as replacement therapy and as therapeutic agents. With continued refinement in recombinant protein technology, the cost of human recombinant proteins may become more affordable. As more novel human recombinant enzymes are developed, a wide variety of medical disorders will be amenable to enzyme therapies. Additional molecular engineering such as pegylation or creation and modification of... 

There is considerable interest in the design of highly specific irreversible enzyme inhibitors because of their potential use as therapeutic agents. Part of the research program of most pharmaceutical companies is the rational design of drugs based on mechanistic ideas from enzymology, biochemistry, and chem-... 

Vanadium has marked influences on cellular growth, cellular oxidation-reduction, and enzyme function. The metal is part of the active site of some enzymes, widely believed to be a required ultra trace nutrient, and is toxic in large amounts. The development of vanadium complexes as therapeutic agents for diabetes and cancer is being actively pursued. Much of the influence of vanadium on biological processes... 

In 1994 Merck researchers disclosed the design and pharmacologic properties of orally bio-available HIV-PR inhibitor L-735,524 (9), which eventually became known as therapeutic agent Indinavir and was commercialized as Crixivan .16-22 It was hypothesized that incorporation of a basic amine, present in the potent HIV-PR inhibitor Ro 31-8959 (10, Saquinavir ), into the backbone of the L-685,434 series would improve the bioavailabiUty of these compounds. Replacement of P2/P ligand of 2 (Af-Boc and phenyl moieties) by the P27P/ ligand of 10 (decahydroisoquinoline tert-butyl amide) was envisioned to enhance aqueous solubility of the series. Despite the high enzyme-inhibitory... 

By one year post liver transplant both CYP expression and activity are similar to those of normal subjects [67]. Some interesting effects are observed in the first six months after transplant, but some may be due to the induction of specific enzymes by therapeutic agents used in this period. The observation of a tenfold increase in hepatic CYP3A4 content at ten days which then returns to normal at six months is probably due to the administration of prednisolone in the early postoperative period [69]. Other observations are more difficult to explain. An eightfold increase in CYP2E1 as measured by the chlorzoxazone metabolic ratio has been detected in the first month post transplant [70]. CYP2E1-mediated NAPQI formation from paracetamol is also increased by around 137% and 81% on days two and ten post transplant, and returns to normal after six months [71]. 

Focusing on the postprenylation enzymes Reel and Icmt is an attractive approach for the development of potential therapeutic agents, especially in refractory solid tumors because their enzymatic functions are unique. Inhibitors for the endoprotease have arisen mainly from the design of substrate-based compounds however, their therapeutic use may be in question because of the recent data indicating the importance of Reel function. On the other hand, inhibitors of Icmt demonstrate promise as therapeutic agents. 

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