Short-chain peptides

Peptides—Short chains of amino acids small proteins. 

Peptides (short chains of amino acids, see Section 3.6.3), comprise the classes of hormones, neurotransmitters, endorphins, and growth factors. They are produced and stored in the nervous system, endocrine system, and immune system (Capra, 1996). They are physiologically active, and increase attention, raise glucose levels, increase heart rate, and deaden pain, among others. 

Short chains of amino acid residues are known as di-, tri-, tetrapeptide, and so on, but as the number of residues increases the general names oligopeptide and polypeptide are used. When the number of chains grow to hundreds, the name protein is used. There is no definite point at which the name polypeptide is dropped for protein. Twenty common amino acids appear regularly in peptides and proteins of all species. Each has a distinctive side chain (R in Figure 45.3) varying in size, charge, and chemical reactivity. 

There have been notable successes in the replacement of individual peptide residues by peptoid monomers with retention of in vitro activity and enhancement of specificity. Unfortunately, attempts to completely transform those bioactive peptides that function via specific peptide-protein binding events into entirely pep-toid-based ohgomers have so far proven successful only at short chain lengths (e.g. [23]). It remains to be seen whether any general strategy can be developed in... 

In 1996, research groups led by Gellman and Seebach, independently reported that enantiopure short chain y9-peptides with an appropriate substitution pattern (oligomer of /9-substituted /9-amino acids 1 [10] and oligomer of trans-2-amino-cy-clohexane carboxylic acid (trans-AGHG) 2 [6], respectively) could fold in a predict-... 

The recognition that short chain / -peptides can form regular secondary structures initially came from detailed conformational analysis of y9 -peptides 1 and 66 (which incorporates a central (2S,3S)-3-amino-2-methylbutanoic acid residue) by NMR in pyridine-d5 and CD3OH [10, 103, 164] and homooUgomers (as short as four residues) of trons-2-amino-cyclohexanecarboxyhc acid (trans-ACHC) (e.g. hex-amer 2 for the (S,S) series) by NMR and X-ray diffraction [6, 126, 159]. 

While conformation II (Fig. 2.34) of Uke-y -amino acids is found in the 2.614-helical structure, conformation I, which similarly does not suffer from sy -pen-tane interaction, should be an appropriate alternative for the construction of sheet-like structures. However, sheet-like arrangement have not been reported so far for y-peptides composed of acyclic y " -amino acid residues. Nevertheless, other conformational biases (such as a,/9-unsaturation, cyclization between C(a) and C(y)) have been introduced into the y-amino acid backbone to restrict rotation around ethylene bonds and to promote extended conformation with formation of sheets in model peptides. Examples of such short chain y-peptides forming antiparallel (e.g. 152 [208]) and parallel (e.g. 153-155 [205, 208]) sheet-hke structures are shown in Fig. 2.38. 

Seebach, D., Ciceri, P. E., Overhand, M.,Jaun, B., Rigo, D., Oberer, L., Hommel, U., AmsUttz, R., and Widmer, H. (1996). Probing the helical secondary structure of short-chain /3-peptides. Helv. Chim. A da 79, 2043-2066. 

Amidation refers to the replacement of a protein s C-terminal carboxyl group with an amide group (COOH — CONH2). This PTM is usually characteristic of peptides (very short chains of amino acids), as opposed to the longer polypeptides, but one therapeutic polypeptide (salmon calcitonin, Chapter 11) is amidated, and amidation is required for full functional activity. Overall, the function(s) of amidation is not well understood, although in some cases at least it appears to contribute to peptide/polypeptide stability and/or activity. 

Peptides are short chains of amino acids linked by peptide bonds. Most biologically active peptides contain two to ten amino acids. Peptide bonds are formed between the carboxyl carbon of one amino acid and the amino nitrogen of another. Since water is released, this is an example of dehydration synthesis. The bond forms as illustrated in Figure 16.7. 

In the first phase of their research, Squibb tested a short-chain peptide isolated from the venom of the viper Bothrops jararaca, with which Vane was working in the laboratory, in human volunteers and showed that it did, indeed, inhibit the conversion of angiotensin I to angiotensin II after intravenous injection. The peptide was also shown to reduce blood pressure in patients when injected. Since the vast majority of peptides cannot be absorbed from the GI tract, Squibb scientists set out to prepare a nonpeptide compound that could be used orally and manufactured at acceptable cost. The design of a true peptidomimetic that became orally active had not been accomplished at that time. Squibb then carried out... 

The words peptide and polypeptide are both used to describe chains of amino acids linked by peptide bonds. Peptides are short chains of amino acids that do not form part of a protein. The number of amino acids is indicated by a prefix (e.g. dipeptide, hexapeptide, oligopeptide). Polypeptides (or polypeptide chains) are longer sequences which can form part of a protein, which may consist of several polypeptides (Appendix 3.1). 

Kawasaki T, Seki E, Osajima K, Yoshida M, Asada K, Matsui T, Osajima Y. (2000) Antihypertensive effect of valyl-tyrosine, a short chain peptide derived from sardine muscle hydrolyzate, on mild hypertensive subjects. 

The identification of the first small molecule HDAC inhibitors in the late seventies triggered an exponential growth in medicinal chemistry activity. Three decades and many thousand compounds later, the availabiUty of diverse HDAC inhibitors such as short-chain fatty acids, hydroxamic acids, benzamides and tetracyclic peptides, has not only enabled the elucidation of the catalytic mechanism underlying the deacetylating capacity of HDACs, but has also assisted in the investigation of the biological role of the various HDAC subtypes. Furthermore, HDAC inhibitors are currently being evaluated in the clinic and have shown therapeutic potential in the treatment of cancer. 

Peptides are short chains of amino acids. By combining in various ways, two or more of the over 20 amino acids that are made by ail cells, a very large amount of chemical diversity can be generated. Some species of simple organisms such as the bacteria and the cyanobacteria make a number of distinct peptides, each species producing a different mixture. Some of these molecules have been shown to possess biological activity in certain test systems hence these peptides could be considered as NPs. Interestingly, the biosynthesis of these peptides has been compared, as has the biosynthesis of other NPs (see Chapter 5), with nature s version of the chemist s attempts to maximise the production of chemical diversity. ... 

Figure 12.10 Formation of a silver nanowire inside a channel of a short-chain diphenylalanine peptide tube.

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