Peptide drugs naturally occurring

HPLC is widely used for the analysis of drugs, biogenic amines, steroids, and other low-molecular-weight substances in biological fluids. It has also been used with considerable success in the separation of peptides, both naturally occurring and synthetic, and some examples are collected in Table 3. Particular advantages of HPLC analyses are (a) ver-... 

O DONAHUE has isolated a naturally occurring peptide from brain that can produce responses similar to PCP when administered to animals. The results are reminiscent of the early studies of the opiopeptides that interact with opiate receptors and produce effects like narcotic drugs when administered to animals. 

Figure 3.1 Peptidomimetic chemistry attempts to produce a non-peptidic drug to mimic a bioactive peptide. In Step A, the smallest bioactive fragment of the larger peptide is identified in Step B, a process such as an alanine scan is used to identify which of the amino acids are important for bioactivity in Step C, individual amino acids have their configuration changed from the naturally occurring L-configuration to the unnatural D-configuration (in an attempt to make the peptide less naturally peptidic ) in Step D, individual amino acids are replaced with atypical unnatural amino acids and amino acid mimics in Step E the peptide is cychzed to constrain it con-formationally finally, in Step F, fragments of the cyclic peptide are replaced with bioisosteres in an attempt to make a non-peptidic organic molecule.

Peptide antibiotics are compounds containing amino acids that are covalently linked to other chemical entities and consist of more than one component. In contrast to naturally occurring proteins that are built up from L-amino acids only, peptide antibiotics usually contain o-amino acids. Avoparcin, bacitracin, efroto-mycin, enramycin, thiopeptin, and virginiamycin constitute the main members within this group of drugs (Fig. 6.2). They are usually added to animal feeds at low concentrations, and produce residues in tissues at very low or undetectable levels. Unfortunately, the metabolic pathways of most peptide antibiotics have not been still elucidated. Within the European Union, these antibiotics are regulated under a separate legislation (Directive 70/524/EEC). 

The discovery of a multitude of naturally occurring, bioactive peptides has generated a rich source of pharmacophores from which medicinal chemists are developing new useful therapeutic drugs. After binding to an enzyme, or a membrane receptor, peptide-based inhibitors, neurotransmitters, immunomodulators, and hormones influence cell-to-cell communications and control a variety of vital functions such as metabolism, immune defense, digestion, respiration, sensitivity to pain, reproduction, and behavior. 

Though naturally occurring peptides based on coded amino acids have been widely used as drugs, there are problems with the use of peptides as therapeutic agents. The problems mainly arise from their rapid metabolism by proteolysis, and their interactions at multiple receptors. As a result, peptide researchers have sought modifications of peptide structures to create more stable and bioavailable molecules. P-27 ... 

Special carrier molecules exist for certain substances that are important for cell function and too large or too insoluble in lipid to diffuse passively through membranes, eg, peptides, amino acids, glucose. These carriers bring about movement by active transport or facilitated diffusion and, unlike passive diffusion, are saturable and inhibitable. Because many drugs are or resemble such naturally occurring peptides, amino acids, or sugars, they can use these carriers to cross membranes. 

On the other hand, depsides are peptide analogs entirely build up by hydroxyl acids mutually connected through ester bonds. A representative example of depsides is the naturally occurring macrotetralide antibiotic nonactin (63). Nonactin has been shown to possess activity against the P170-glycoprotein efflux pump associated with multiple drug-resistant cancer cells. 

Naturally occurring peptides are substrates of enzymes and ligands of receptors. Many peptides serve as neurotransmitters and hormones. Because they control a variety of physiological processes, they are also implicated in different diseases. For several reasons peptides are usually unsuitable as drugs, so many efforts in medicinal chemistry aim at the development of peptidomimetics with improved properties. In contrast with proteins most peptides of small to medium size - 30 to... 

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