Natural peptides

Recently, a variety of natural peptides that form transmembrane channels have been identified and characterized. Melittin (Figure 10.35) is a bee venom toxin peptide of 26 residues. The cecropins are peptides induced in Hyalophora cecropia (Figure 10.36) and other related silkworms when challenged by bacterial infections. These peptides are thought to form m-helical aggregates in mem-... 

Since most aaAAs are hydrophobic in nature, peptides rich in aaAAs are generally restricted to study in organic solvents due to their low solubility in aqueous media. There have been very few examples of side-chain functionalized aaAAs that would allow for the synthesis of highly water-soluble peptides rich in aaAA content.3 This is primarily due to difficulty of synthesis, since side-chain functionalized derivatives must be orthogonally protected to allow for incorporation into solid-phase peptide synthesis. The harsh conditions, under which standard methods of aaAA synthesis are performed, make this a difficult task. 

However, most natural peptides are composed of L-form a-amino acids and because of the ubiquitous prevalence of peptidases they have limited biostability, and consequently low bioavailability. Thus, a novel field of peptidomimetics has emerged in drug discovery, in attempts to design non-peptide compounds mimicking the pharmacophore and thus the activity of the original peptide. 

This field has also inspired the development of a range of pseudo-peptides, that is polyamides composed of amino acids other than a-amino acids. These include for instance peptoids, /9-amino acid oligomers and also compounds such as peptide nucleic acids and DNA binding polyamides, all of which share the amide (peptide) chemistry with natural peptides. 

This peptide itself has no selectivity for the two CCK receptors, CCK-A and B, which have so far been established to stimulate IP3/DAG while, like substance P, can close potassium channels to increase neuronal activity. The CCK-B receptor is thought to predominate in the CNS but species differences may make this interpretation difficult. It has a wide distribution in the CNS but is also found in the gut whereas the CCK-A receptor is more restricted but is found in the hypothalamus, hippocampus and in the brainstem. There are high levels of the natural peptide, CCK-8 in cortex, hippocampus, hypothalamus, ventral tegmentum, substantia nigra, brainstem and spinal cord. CCK is one of the most abundant peptides in the brain and CCK co-exists with dopamine, substance P, 5-HT and vasopressin. Interestingly, in the dopamine areas, CCK co-exists in the mesolimbic pathways but in the nigrostriatal projections, the peptide and... 

In the previous section, we have examined peptides composed of nonpro-teinogenic amino acids, namely artificial, D-, f3-, and y-amino acids. In this section, we move even further afield from natural peptides. Given inconsistent usage in the literature, we begin by specifying the definitions used here [7][11][139][181][182][184-188][229]. 

Host defense peptide hydrophobicity (H) is defined as the proportion of hydrophobic amino acids within a peptide. Typically, these peptides are comprised of >30% hydrophobic residues and this governs the ability of a host defense peptide to partition into the lipid bilayer, an essential requirement for antimicrobial peptide-membrane interactions. Typically, the hydrophobic and hydrophilic amino acids of natural peptides are segregated to create specific regions or domains that allow for optimal interaction with microbial membranes. This likely represents evolutionary optimization to maximize the selectivity of these defense molecules. It has been established that increasing antimicrobial peptide hydrophobicity above a specific threshold correlates... 

In contrast, Snyder has demonstrated that an RI derivative ofp53 can restore endogenous p53 activity the RI derivative induced apoptosis by activation of endogenous p53 and by restoration of function to several p53 DNA contact mutants. Rl-modified peptides have also been investigated as potential alternatives for bost defense peptides. Indeed, a RI derivative of indolicidin retained tbe antimicrobial and antiendotoxic acitivities of the natural peptide. As the antiendotoxin activities of the Rl-derivative were conserved these results might indicate the conservation of multiple immunomodulatory activities upon retro-inversion, highlighting the potential of this modification for therapeutic applications. 

The previous examples highlight some of the present technologies being applied for construction of host defense peptides with increased stability and retention of natural peptide activity. Similarly, the examination of host defense peptide candidates has also focused on the identification of methodologies that increase the cost effectiveness of present screening techniques and are also able to examine peptides in a high-throughput fashion. 

Pain relief morphine mimics natural peptides called endorphins... 

In marked contrast to the ribosomal biosynthesis of peptides and proteins where a biological production line interprets the genetic code of mRNA, many natural peptides are known to be synthesized by a... 

Peptide hormones and neurotransmitters are primary agents of communication between different cell types In the body of complex living systems Including man. Thus, analogs of natural peptide hormones and neurotransmitters with appropriate properties have exceptional potential as drugs. Despite this potential and the need for peptide drugs, development has been slow. Why ... 

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. 

In Fig. 3 the sequences of 12 modified as well as two natural peptides which serve as control sequences are given [54]. The diastereomers of all Tfm-substituted peptides were separately studied regarding their protease stability. The results of this hydrolysis study are summarized in Fig. 4. 

Peptoids are N-substituted oligoglycines whose carbonyl and side-chain residues are superimposable to those of natural peptides. Scheme 19 illustrates the structural similarities between both N- and 0-linked glycopeptoids in relation to their analogous glycopeptides. 

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