Peptide bond isosteres

These oligomers for which synthetic routes have been developed, are formally obtained by either the introduction of a peptide bond isostere (e.g. y9-thiopeptides [263],... 

Another major site of peptide metabolism is the blood and especially blood serum and plasma. From an extensive compilation of peptide tm values (over 100 peptides, plus derivatized and cyclized analogues, D-amino acid stereoisomers, peptide bond isosteres, etc.), it appears that the differences between serum, heparinized plasma, and whole blood are fairly limited [161]. Interspecies differences are larger, particularly between humans and rats, with most human/rat t1/2 ratios ranging from 1 1 to 25 1 ... 

Various EADIs have been synthesized using different synthetic routes [30-34], One of the widely used methods of preparation of E-alkene peptide bond isosteres involving ring opening of vinyl aziridines by cuprates has recently been reviewed [35,36],... 

T.C. Henninger, P. Wipf, ( )-Alkene peptide bond isosteres by cuprate opening of vinyl aziridines. Methods Mol. Med. 23 (1999) 125-136. 

Peptidomimetics are peptide molecules characterized by modifications to the side chain (Section 9), to the a-carbon (Sections 10.3 and 10.4), or, to the components of a peptide bond itself either singularly (e.g., Sections 10.1 and 10.2), or, in combination. Peptidomimetics containing a modification to the nature of the peptide bond are often referred to as pseudopeptides or peptide bond surrogates. 1 These compounds are sometimes termed as peptide bond isosteres, although the isosteric nature of the replacement is often not obvious or may even be dubious. 

Bock, V. D., Speijer, D., Hiemstra, H., and van Maarseveen, J. H. (2007) 1,2,3-Tria-zoles as peptide bond isosteres Synthesis and biological evaluation of cyclotetrapeptide mimics. Org. Biomol. Chem. 5, 971-975. 

This modification seems to mimic the presumed tetrahedral intermediate involved in the aspartyl protease-catalyzed hydrolysis of the peptide bond. A HIV-1 protease inhibitor containing a hydroxyethylene bond isostere has been prepared on solid phase [143]. A Boc-N-protected bromomethyl ketone was coupled to the resin-bound N-free Pro-Ile-Val tripeptide, and the keto function was reduced to an OH group with NaBH4.The peptide analogue was then elongated on the resin.This procedure allows rapid access to a variety of hydroxyethylamino peptide bond isosteres, and in good yield. 

Hydroxyethylene dipeptidc isosteres 35, which are of interest as transition state analogs, e.g., in renin inhibitors where they replace the scissile dipeptide unit (Leu-Val) of angiotensinogen, the natural substrate of renin, can be obtained from optically active acid 32 via iodolactoniza-tion in several steps. The synthesis of 32 is achieved using an Ireland - Claisen rearrangement as the key step which allows complete control of the three stereogenic centers44. For a stereocontrolled synthesis of peptide bond isosteres via Claisen rearrangements see also ref 448. 

The ( )-i/r[CH2=CH2] peptide bond isostere is a rigid nonhydrolyzable moiety that effectively mimics the amide bond structure (the distance... 

The growing interest in sulfonamides as peptide bond isosteres is motivated by their increased resistance to enzymatic degradation, by their structural similarity to the tetrahedral transition state intermediate, and thus by their... 

Most HIV-PR inhibitor designs have focused on transition state analogues, i.e. analogues based on the known sequences of peptide substrates, but with the scissile bond replaced by a peptide bond isostere. Among the most effective peptide bond isosteres introduced into HIV-PR inhibitors have been the hydroxyethylene and hydroxyethyl-amine moieties (Fig. 20.7), in both of which the isosteric hydroxyl group is thought to mimic the tetrahedral... 

Copper-catalyzed azide-alkyne cycloadditions have become increasingly popular due to their almost quantitative formation of 1,4-substituted triazoles, regioselectively, and the remarkable functional group tolerance, which is important when dealing with peptides or peptidomimetics. The majority of publications on dipolar cycloaddition reactions in peptide chemistry has focused on the CuAAC and reported peptide bond isosteres, side-chain functionalization, glycoconjugation, macrocyclization and isotopic labeling of peptides. We will most likely see an inaeasing number of applications where peptides are modified by dipolar cycloadditions in the future. 

Alel992 Alewood, P.F., Brinkworth, R.I., Dancer, R.J., Gamham, B., Jones, A. and Kent, S.B.H., Solid Phase Synthesis of Hy-droxyethylamine Peptide Bond Isosteres Synthesis of the Potent HrV-1 Protease Inhibitor JG365, Tetrahedron Lett., 33 (1992) 977-980. 

Hoc 1990 Hocart, S.J., Murphy, W.A. and Coy, D.H., Analogues of Growth Hormone-Releasing Factor (1-29) Amide Containing the Reduced Peptide Bond Isostere in the N-Terminal Region, J. Med. Chem., 33 (1990) 1954-1958. 

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