Mimetics

Therapy for insulin-dependent diabetes mellitus is usually achieved by daily subcutaneous injections of insulin, and insulin-mimetics which can be orally administered may be useful for the treatment of type I diabetes (insulin dependent) if suitable complexes of low toxicity can be identified (510, 511). 

It was discovered nearly 20 years ago that V(V) as vanadate and V(IV) as vanadyl can mimic some of the effects of insulin (stimulate glucose uptake and oxidation and glycogen synthesis) (512, 513). Vanadate is an effective insulin mimetic in the diabetic rat (514), but has proved to be too toxic for human use. Vanadyl, as VOS04, is also unsuitable because high doses are needed on account of its poor oral absorption. Vanadium complexes with organic ligands have proved to be less toxic and can have improved aqueous solubility and lipophil-icity. 

Sakurai et al. have observed that vanadyl complexes with coordination modes such as VO(S4) (103) can normalize blood glucose levels (515) and are effective for normalizing both serum glucose and free fatty acid levels in streptozotocin rats and are orally active (516). Bis(picolinato)oxovanadium(IV) is also orally active against the diabe- 

Peroxovanadates are effective at much lower doses (ca. 100-fold) than vanadate itself, but readily decompose in aqueous solution and must be administered by injection. Posner et al. have shown that organic ligands can stabilize peroxo complexes and that peroxovanadate complexes such as 105 (with L-L = e.g., phenanthroline, picolinate, 

Orvig et al. (522) have shown that the orally active bis(maltolato) oxovanadium(IV) complex 106 (BMOV) is 3 times more effective in 

Collagen, a class of fibrous protein, is the most abundant protein in the human body, accounting for approximately 25% of the total protein mass. It is the main component of the ECM and serves as a stmctural protein in connective tissues, such as skin, bone, cartilage, and blood vessels. Twenty-eight types of collagen have been identified in humans to date (Kar et al. 2006). Among these, collagen types I-III are the most abundant. 

AggeU A, BeU M, Boden N, Camck LM, Strong AE. Self-assembling peptide polyelectrol3de beta-sheet complexes form nematic hydrogels. Angew Chem Int Ed 2003 42 5603-5606. 

Aggeli A, BeU M, Boden N, Keen JN, Knowles PE, Mcleish TCB, Pitkeathly M, Radford SE. Responsive gels formed by the spontaneous self-assembly of peptides into polymeric 8-sheets tapes. Nature 1997 386 259-262. 

Aggeli A, BeU M, Carrick LM, Eishwick CWG, Harding R, Mawer PJ, Radford SE, Strong AE, Boden N. pH as a trigger of peptide j8-sheet seU-assembly and reversible switching between nematic and isotropic phases. J Am Chem Soc 2003 125 9619-9628. 

Antzutkin ONB, John J, Leapman RD, Rizzo NW, Reed J, Tycko R. Multiple quantum soUd-state NMR indicates a parallel, not antiparallel, organization of /8-sheets in Alzheimer s /3-amyloid fibrils. Proc Natl Acad Sci USA 2000 97 13045-13050. 

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Protein acidulant Protein additives Protein ammo acids a-l-Proteinase inhibitor Protein-based mimetics Protein Ca [42617-41-4] Protein channels Protein chromatography Protein crystal growth... 

One frozen dessert is made with Simplesse, a protein-based fat mimetic that contains no fat (37). Other dairy product developments include a fat flavor, produced by encapsulating milk fatty acids in maltodextrins (38) fat-free cottage cheeses and 2% fat milk, prepared by steam stripping cream with partial fat addback, with a cholesterol level about 60% lower than the starting material (39). 

Two classes of fat replacers exist mimetics, which are compounds that help replace the mouthfeel of fats but caimot substitute for fat on a weight for weight basis and substitutes, compounds having physical and thermal properties similar to those of fat, that can theoretically replace fat in all appHcations (46). Because fats play a complex role in so many food appHcations, one fat replacer is often not a satisfactory substitute. Thus a systems approach to fat replacement, which reHes on a combination of emulsifiers, gums, and thickeners, is often used. 

Fa.tMimetics. Existing fat mimetics are either carbohydrate-, ceUulosic (fiber)-, protein-, or gum-based. These are used in a wide variety of appHcations including baked goods, salad dressings, frozen desserts, meats, confections, and dairy products. Table 3 Hsts some of the commercially available fat mimetics. 

PaseUi-SA-2 potato Carbohydrate-based mimetics Avebe... 

N-Oil corn Celluhsic-based mimetics National Starch... 

O a trim oats Protein-based mimetics Rhc ne-Poulenc/Quaker Oats ConAgra... 

Tradblazer whey/milk protein Gum-based mimetics Kraft General Foods... 

Use of D-amino acids in the synthesis of a hairpin loop portion from the CD4 receptor provides a stable CD4 receptor mimic, which blocks experimental allergic encephalomyelitis (144). This synthetic constmct is not simply the mirror image or enantiomer of the CD4 hairpin loop, but rather an aH-D-constmct in the reverse sequence, thus providing stereochemicaHy similar side-chain projections of the now inverted backbone (Fig. 11). This peptide mimetic, unlike its aH-L amino acid counterpart, is resistant to en2yme degradation. As one would expect, the aH-D amino acid CD4 hairpin loop, synthesi2ed in the natural direction, the enantiomer of the natural constmct, is inactive. 

Methylpyrazole has been investigated as a possible treatment for alcoholism. The stmcture—activity relationship (SAR) associated with a series of pyrazoles has been examined ia a 1992 study (51). These compounds were designed as nonprostanoid prostacyclin mimetics to inhibit human platelet aggregation. In this study, 3,4,5-triphenylpyrazole was linked to a number of alkanoic acids, esters, and amides. From the many compounds synthesized, triphenyl-IJT-pyrazole-l-nonanoic acid (80) was found to be the most efficacious candidate (IC g = 0.4 //M). 

In addition to the sex hormones and corticosteroids, other steroid dmgs have substantial worldwide markets. For example, cytostatic hormones had worldwide sales of approximately 1.8 biUion in 1994. Included in these 1.8 biUion are several steroids or steroid-mimetics such as megestrol acetate and tamoxifen (282), respectively (262). 

Wrighton, N.C., et al. Small peptides as potent mimetics of the protein hormone erythropoietin. Science 273 458-463, 1996. 

Standards are needed to find M " 1 monolayer of mimetic material 20—40 nm... 

The hydantoin moiety has been utilized as a biostere for the peptide linkage, transforming a peptide lead into an orally available drug candidate. Therefore, an Arg-Gly-Asp-Ser tetrapeptide (18) lead structure was modified to a non-peptide RGD mimetic as an orally active fibrinogen receptor antagonist 19. ° ... 

Carbohydrate mimetics including heterocyclic fragments and a new strategy for tackling the problem of biological recognition with participation of carbohydrates 99AG(E)2300. 

Fendler, J. H. Membrane Mimetic Chemistry, John Wiley Sons, New York 1982... 

Fendler J (1983) Membrane mimetic chemistry. Academic press, New York... 

Incretin mimetic Exenatide Mimic GLP-1C enhance prandial insulin secretion SC injectiond... 

Incretin mimetic Severe renal or gastrointestinal disease Nausea, hypoglycaemia if used with another antidiabetic agent b... 

Anti-cytokines (e.g. IL-1, TNFs, IL-1 receptor constructs) Prostaglandins and PG mimetics... 

Erd41yi M (2002) Development of new mimetics for fS-hairpins. Philosophy Licentiate Thesis. Uppsala University, Sweden... 

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