Peptides, immunosuppressant synthesis

Many antibiotics, which inhibit protein synthesis, do not bind to ribosomes but block any of a variety of vital chemical processes needed for growth. Among them are pseudomonic acid, which inhibits isoleucyl-tRNA synthetase from many gram-positive bacteria.1111/VV Rapamycin, best known as an immunosuppressant (Box 9-F), inhibits phosphoinositide-3-kinase and also phosphorylation of the cap-binding protein 4G, a component of the eukaryotic initiation factor complex (Fig. 29-11 ).ww The bacterial enzyme peptide deformylase, which is absent from the human body, has been suggested as a target for design of synthetic antibiotics. 01... 

Peptide chemists are becoming increasingly interested in the synthesis of immunosuppressive and immunostimulating peptides, which are discussed below. 

Some antibiotics that have been derived from peptides were mentioned in Chapter l. The biosynthesis of penicillins was discussed in Chapter 8. Many peptide antibiotics are known. Some find clinical applications but others such as gramicidin S (9.7), tyrocidine A (9.8) and polymyxins (9.9) are too toxic for use in humans. Cyclosporin A (Figure 1.4), however, has immunosuppressive properties and it has been used in transplant surgery for this reason rather than for its antibiotic properties. Peptide antibiotics have some non-standard structural features and these may explain in part their antibiotic properties. First, cyclic peptides are not found in animal cells. Secondly, peptide antibiotics usually contain some unusual amino acids they may have the d configuration, be A-methylated or have other non-standard structural features. Clearly, these features are not compatible with direct ribo-somal synthesis. 

Kahn, M., and Devens, B., The design and synthesis of a nonpeptide mimic of an immunosuppressing peptide. Tetrahedron Lett., 27, 4841, 1986. 

A number of cytokines also play important roles in regulating other processes that might contribute to immunosuppression. SIL-2R is released by T lymphocytes stimulated to proliferate by IL-2. IL-1 and TNF induce the synthesis and release of proteinases that might contribute to the production of trauma-derived peptides. The effects of sIL-2R and trauma-derived peptides are probably particularly important at or close to the site of production that is they are acting in a paracrine fashion. 

C5 H,9N0,3, Mr914.19, cryst., mp. 183-185°C, [aJu -58.2° (CH3OH), a 31-membered peptide lactone in which a long-chain carboxylic acid is cyclized with l- pipecolic acid as a bridge and produced by Strepto-myces hygroscopicus. R. has antifungal, antineoplastic, and immunosuppressive activities, it is structurally related to FK-506 and exhibits a similar mechanism of action in the development of the immune response. R. was first marketed in 1999 in combination with cyclosporin and tacrolimus for use in transplantation medicine. The first total synthesis of R. was realized in 1993. 

As far as cyanobacteria are concerned, cyclic peptides and depsipeptides are more frequent than the linear forms. However, among the latter, microcolins A and B have intense immunosuppressive and antiproliferative properties. These two pentapeptides, isolated from a Lynghya majuscula of Venezuela, differ only in the presence of a hydroxyl on a proline (Koehn, Longley, and Reed, 1992 Zhang, Longley, and Koehn, 1997). The total asymmetrical synthesis of microcolin A was carried out four years after its discovery (Decicco and Grover, 1996), and that of microcolin B one year later (Andrus, Li, and Keyes, 1997). 

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