Peptides, immunosuppressant

Three endogenous opioids have been identified enkephalins, dynorphins and beta-endorphins. These opioid peptides selectively bind to the seven transmembrane GPCRs delta (8), kappa (k), and mu (p). Although dynorphin binds predominately to the k receptor, P-endorphines and enkephalins bind to p and 8 opioid receptors. It is important to note that the analgesia induced by opioids is mediated predominately throngh the p opioid receptor. In vitro studies have shown a decrease in the immnne function and proliferation following p-endorphin administration in rodents (Ray and Cohn 1999) and that the immunosuppressive effects by P-endorphins are steroid-independent (Berkenbosch et al. 1984 Nelson et al. 2000). 

Two structurally unrelated immunosuppressant drugs, cyclosporin A and FK506, have been shown to bind to separate proteins, which have in common the ability to catalyse the interconversion (8) of the cis and trans rotamers of peptidyl-proline bonds of peptide substrates. A profound change in the conformation, and hence the shape and binding properties of the protein, may result. The mechanism of this isomerization appears, on the basis of recent work (Rosen et al., 1990 Van Duyne et al., 1993 Albers et al., 1990), to involve simple twisting about the amide bond, rather than such alternatives as conversion to a C-N single bond by addition of a nucleophile to C=0.y The proteins which catalyse the reaction may be... 

Figure 23.3 Drug transporters in the intestinal epithelial cells. PEPT1 is the most characterized transporter for intestinal drug absorption. The basolateral peptide transporter, which is not identified at the molecular level, also plays important roles. OATP-B, OCTN2 and MRP3 may be responsible for the intestinal absorption of some drugs. On the contrary, ABC transporters such as P-gp located at brush-border membranes mediated the efflux of drugs from intestinal epithelial cells, contributing to the low bioavailabihty of drugs such as the immunosuppressive agent, tacrolimus.

H Fungi - Amanita phalloides and Agaricus phalloides Cyanobacteria -Lyngbya majuscula Phalloidin, phallicidin, and amanitin - toxic peptides Majusculamide D - cytotoxic peptide Microcolin A - peptide with immunosuppressive, antileukemic and protein kinase C inhibitory activity 242... 

The cyclosporins are a group of cyclic peptides produced by fungi such as Cylindrocarpon lucidum and Tolypocladium inflatum. These agents show a rather narrow range of antifungal activity, but high levels of immunosuppressive and anti-inflammatory activities. The main component from the culture extracts is cyclosporin A, but some 25 naturally occurring cyclosporins have been characterized. 

Koehn, F.E. Longley, R.E. Reed, J.K. (1992) Microcolins A and B, new immunosuppressive peptides from the blue-green alga Lyngbya majuscula. J. Nat. Prod., J5, 613-9. 

The introduction of cyclosporin, a peptide derived from a fungus, revolutionised immunosuppressive therapy, and was one of the major influences in the improvement of early graft survival in transplant surgery when introduced in the 1980s. The main action is a relatively selective inhibition of IL-2 production and consequently a decreased proliferation of T cells. A major advantage of cyclosporin is that it does not cause myelosuppression in therapeutic doses. The major side effect is nephrotoxicity, which occurs in about 20% of patients, and about 50% of patients develop moderate hypertension. The other major side effect is hepatotoxicity with cholestasis and hyperbilirubinaemia. 

Hydroxychloroquine is an antimalarial agent with immunosuppressant properties. It is thought to suppress intracellular antigen processing and loading of peptides onto MHC class II molecules by increasing the pH of lysosomal and endosomal compartments, thereby decreasing T-cell activation. 

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... 

CONTENTS Preface. Bruce E. Maryanoff and Cynthia A. Maryanoft. Novel An-tipsychotics with Unique D /5-HT1A Affinity and Minimal Extrapyramidal Side Effect Liability. Allen B. Reitz and Malcolm K. Scott. Antiplatelet and Antithrombotic Agents From Viper Venom Proteins, to Peptides and Peptidomimetics. to Small Organic Molecules, Peter L. Barker and Robert R. Webb. II. Discovery and Preclinical Development of the Serotonin Reuptake Inhibitor Sertraline, Willard M. Welch. Boronic Acid Inhibitors of Dipeptidyipeptidase IV A New Class of Immunosuppressive Agents, Roger J. Snow. Index. 

Cyclosporins, produced by the filamentous fungus Tolypocladium niveum and by numerous strains of Fusaria and Neocosmospora, are a class of cyclic undecapep-tides which are composed of hydrophobic aliphatic amino acids [73-75], They exhibit antiinflammatory, immunosuppressive, antifungal, and antiparasitic properties [74], The main metabolite, cyclosporin A, is in clinical use worldwide under the trade name SANDIMMUN to prevent allograft rejection [77,78], Besides cyclosporin A, there are 24 naturally occuring cyclosporins which have substitutions of amino acids in positions 1, 2, 4, 5, 7, and 11 and/or contain unmethylated peptide bonds in positions 1,4,6,9,10, or 11 [79-82], Cyclosporin A contains three nonproteinogenic amino acids D-alanine in position 8, L-a-aminobutyric acid in position 2, and, in position 1, the unusual amino acid 4(R)-4-[(E)-2-butenyl]-4-methyl-L-threonine (Bmt) (Fig. 8). All three amino acids have to be synthesized by a pathway independent of the primary metabolism. In addition, several peptide bonds of the cyclosporin molecule are A -mcthylated similar to the depsipeptides enniatin, beauvericin and PF1022A-related peptides. 

---