Protein drugs enzymes

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

A topic of actuality is the study of receptor proteins and enzymes for which data bases with crystallographic information are now made available. Computer modelling of the active sites of receptors and enzymes are important tools in rational drug design. Principal components and cluster analysis can be applied to the primary... 

Persons with mutations that partially destroy G6PDH activity may develop an acute, episodic hemolysis. Certain mutations affect the stability of G6PDH, and, because erythrocytes cannot synthesize proteins, the enzyme is gradually lost over time and older red blood cells lyse. This process is accelerated by certain drugs and, in a subset of patients, ingestion of fava beans. In the United States, the most likely cause of a hemolytic episode in these patients is overwhelming infection, often pneumonia (viral and bacterial) or infectious hepatitis. 

Further, drug absorption, distribution, and elimination from the body may vary due to differences in protein binding, enzymic modification, etc, since proteins are also chiral entities (see Chapter 13). 

In recent years, RMs were reported to be applicable in diverse areas other than proteins and enzymes, which deserve a note here. These include extraction and determination of metals and metal ions, photoinduced electron transfer, RMs in supercritical liquids, extraction of antibiotics/drugs, synthesis of nanoparticles, etc. 

Protein drugs have been formulated with excipients intended to stabilize the protein in the milieu of the pharmaceutical product. It has long been known that a variety of low molecular weight compounds have the effect of preserving the activity of proteins and enzymes in solution. These include simple salts, buffer salts and polyhydroxylated compounds such as glycerol, mannitol, sucrose and polyethylene glycols. Certain biocompatible polymers have also been applied for this purpose such as polysaccharides and synthetic polymers such as polyvinyl pyrrolidone and even nonionic surfactants. 

Peptidases such as trypsin are also hydrolytic enzymes and are important considerations for the new generation of peptide and protein drugs (see below). 

Figure 5.34 Mechanism of induction of CYP2B6 by a chemical such as the drug phenobarbital. This drug activates a nuclear receptor (CAR).This combines with the retinoid X receptor and binds to PBREM, as specific section of the CYP gene, which stimulates the production of CYP2B6 mRNA leading to the production of CYP2B6 protein and enzyme. Abbreviations CAR, constitutive androstane receptor RXR retinoid X receptor PBREM, phenobarbital-responsive enhancer module.

Affinity chromatography can be applied to the isolation and purification of virtually all biological macromolecules. It has been used to purify nucleic acids, enzymes, transport proteins, antibodies, hormone receptor proteins, drug-binding proteins, neurotransmitter proteins, and many others. 

Aprotinin is a polypeptide consisting of 58 amino acid residues derived from bovine lung tissues and shows inhibitory activity toward various proteolytic enzymes including chymo-trypsin, kallikrein, plasmin, and trypsin. It was also one of the first enzyme inhibitors used as an auxiliary agent for oral (poly)peptide administration. The co-administration of aprotinin led to an increased bioavailability of peptide and protein drugs [5,44,45], The Bowman-Birk inhibitor (71 amino acids, 8 kDa) and the Kunitz trypsin inhibitor (184 amino acids, 21 kDa) belong to the soybean trypsin inhibitors. Both are known to inhibit trypsin, chymotrypsin, and elastase, whereas carboxypeptidase A and B cannot be inhibited [7,46],... 

As mentioned above, the rectal route is very attractive for systemic delivery of peptide and protein drugs, but rectal administration of peptides often results in very low bioavailability due to not only poor membrane penetration characteristics (transport barrier) but also due to hydrolysis of peptides by digestive enzymes of the GI tract (enzymatic barrier). Of these two barriers, the latter is of greater importance for certain unstable small peptides, as these peptides, unless they have been degraded by various proteases, can be transported across the intestinal membrane. Therefore, the use of protease inhibitors is one of the most promising approaches to overcome the delivery problems of these peptides and proteins. Many compounds have been used as protease inhibitors for improving the stability of various peptides and proteins. These include aprotinin, trypsin inhibitors, bacitracin, puromycin, bestatin, and bile salts such as NaCC and are frequently used with absorption enhancers for improvement in rectal absorption. 

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