Peptides as Drugs

Trade name Corresponding peptide or smaii protein Moiecuiar mass (kDa) Company Indication Sales (2002) million US  

Betas eron Interferon-P 23 Schering Multiple Sclerosis 740 

Glucagon Glucagon 3.5 Novo Nordisk Hypo- glycaemia 110 

Forteo Teriparatide [human parathyroid hormone (1-34)] 6 Eli Lilly Osteoporosis 2000 

Genotropin/ Somatropine Human growth hormone 22 Pfizer Dwarfism 551 

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There are a number of problems associated with the use of peptides as drug molecules. Peptides are rapidly degraded by proteases and, therefore, their biological half lives are normally too short to be useful In a therapeutic sense. Most peptides exhibit more than one type of biological effect making lack of specificity a problem to be overcome. The size of even "small" peptides Is larger than most common drug molecules, and it is usually desirable, if for no other reason than ease of synthesis, to simplify the structures as much as possible. Finally, for the small number of peptides which have been studied by the oral route, poor bloavallablllty has been a problem. 

Although they are potent endogenous bioactive molecules, peptides rarely make good drugs. There are several reasons for the failings of peptides as drugs ... 

The most severe problems exist with peptide ligands, and this is particularly the case for the high-throughput screening of peptide libraries. Once an active peptide has been discovered, it will be necessary to design a suitable non-peptide analogue to avoid the problems of poor absorption and sensitivity to peptidases that confound the direct use of peptides as drugs. It will be necessary to know the conformation of the peptide lead. 

Mizuma, T., A. Koyanagi, and S. Awazu. 1997. Intestinal transport and metabolism of analgesic dipeptide, kyotorphin Rate-limiting factor in intestinal absorption of peptide as drug. Biochim... 

Already most bioactive peptides have been prepared in larger quantities and made available for pharmacological and clinical investigations. Subsequently it became clear that the use of peptides as drugs is limited by the following factors a) their low metabolic stability towards proteolysis in the gastrointestinal tract and in serum b) their poor transport from the gastrointestinal tract to the blood as... 

Groner, B., Ed., Peptides as Drugs. Discovery and Development, John WUey Sons, 2009. 

Instead of using the oral bioavailability of a drug, one can attempt to correlate PM values with permeability coefficients generated from in situ perfused intestinal preparations. Here, one eliminates the complexities of liver metabolism, clearance, and formulation variables. Recently, this type of in vitro-in situ correlation has been conducted using the model peptides (described previously in Section V.B.2). The permeabilities of these model peptides were determined using a perfused rat intestinal preparation which involved cannulation of the mesenteric vein (Kim et al., 1993). With this preparation, it was possible to measure both the disappearance of the peptides from the intestinal perfusate and the appearance of the peptides in the mesenteric vein. Thus, clearance values (CLapp) could be calculated for each peptide. Knowing the effective surface area of the perfused rat ileum, the CLapp values could be converted to permeability coefficients (P). When the permeability coefficients of the model peptides were plotted as a function of the lipophilicity of the peptides, as measured by partition coefficients in octanol-water, a poor correlation (r2 = 0.02) was observed. A better correlation was observed between the permeabilities of these peptides and the number of potential hydrogen bonds the peptide can make with water (r2 = 0.56,... 

Although the ocular absorption of peptide as well as nonpeptide drugs is poor [96,196-198], the ocular route is by far the least studied for the usefulness of penetration enhancers. This is in part due to the perceived sensitivity of ocular tissues to irritation and the fear of corneal and conjunctival damage caused by the enhancers. Whereas the rat nasal epithelium may tolerate up to 5% sodium glycocholate [199], ocular administration of sodium glycocholate at a concentration of 2% and beyond induces reddening of the eye and tear production in rabbits (Kompella and Lee, unpublished observation). 

The subsequent chapters will describe various quantum-chemical methods, compare them to experimental results and discuss their applications to such biological systems as amino acids, peptides, carcinostatic drugs, and DNA fragments. Proteins and large DNA fragments cannot be treated as yet with quantum-chemical methods, due to their size, but progress is being made continuously. 

Proteins, peptides, or carbohydrate products produced by cell culture, excluding antibiotics, hormones, and products previously derived from human or animal tissue regulated as drugs. 

The extent of drug absorption following nasal administration depends to a reasonable extent on the ease with which a drug molecule crosses the nasal epithelium without degradation or rapid clearance by the mucociliary clearance system. The effects of these two elimination components are more pronounced for proteins and peptides. The nasal administration of drugs, especially proteins and peptides, as well as other molecules has been studied with excised tissues harvested from rabbit, cow, sheep, and pig species (Table 5.2). A... 

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