Dipeptides, resistance

One way to gain fast access to complex stmctures are multicomponent reactions (MCRs), of which especially the isocyanide-based MCRs are suitable to introduce peptidic elements, as the isonitrile usually ends up as an amide after the reaction is complete. Here the Ugi-4 component reaction (Ugi CR) is the most suitable one as it introduces two amide bonds to form an M-alkylated dipeptide usually (Fig. 2). The Passerini-3CR produces a typical element of depsipeptides with ester and amide in succession, and the Staudinger-3CR results in p-lactams. The biggest unsolved problem in all these MCRs is, however, that it is stUl close to impossible to obtain products with defined stereochemistry. On the other hand, this resistance, particularly of the Ugi-reaction, to render diastereo- and enantioselective processes allows the easy and unbiased synthesis of libraries with all stereoisomers present, usually in close to equal amounts. 

Asn-Pro, Asp-Met, Asp-Leu, Ala-Val, and Gly-Val were isolated from fermented sardine sauce further, the ACE-inhibitory peptides Ala-Pro, Arg-Pro, Gly-Pro, and Ala-Gly-Pro were isolated from fermented bonito sauce. Val-Pro was also identified in salted and fermented anchovy by Lee (1996). Among the peptides identified by Ichimura et al. (2003), Ala-Pro, Lys-Pro, and Arg-Pro showed strong and similar inhibitory activity. Ichimura et al. (2003) also isolated nine types of peptides containing Pro residues in their carboxy terminals. Due to the unique structure of Pro as an imino acid, peptide bonds containing Pro residues are often resistant to hydrolysis by common peptidases. This may be the reason why these Pro-containing dipeptides survived after long-term fermentation. Among these peptides, Lys-Pro was further evaluated in vivo in male SHRs (Charles River Japan, Yokohama) by oral administration. As shown in Fig. 5.3, orally administered Lys-Pro shows a tendency to lower the blood pressure of SHRs. 

Z Wu, CT Walsh. Phosphinate analogs of D-,D-dipeptides slow-binding inhibition and proteolysis protection of VanX, a D-,D-dipeptidase required for vancomycin resistance in Enterococcus faecium. Proc Natl Acad Sci (USA) 92 11603-11607, 1995. 

Researchers from Takeda have isolated the antibiotics TAN-1057 A-D 29, 30 from Flexibacter sp. [67]. These (S)-/7-Lys-derived dipeptides have promising activity against clinically problematic methicillin-resistant strains of Staphylococcus aureus (MRSA). The /7-amino acid moiety is essential for the biological activity of TAN-1057 A 29. The bisguanidine 29 seems to have a dual mode of action, involving... 

The wild-type UDP-MurNAc-L-Ala-y-D-Glu-L-Lys-D-Ala-D-Ala (UDP-MurNAc-pentapeptide) was first isolated from S. aureus in 1952 by James Park [77], Nicolas Gisch et al. reported the synthesis of the biotinylated Lys-type and DAP-type muramyl tripeptides through their UDP derivatives [78], Both compounds activated Nod2 in a cell-based assay, although the required minimal motif for the activation of Nod2 is muramyl dipeptide [79], The chemical synthesis of the UDP-MurNAc-pentapeptide 7 (Scheme 14.1) [19] was followed by the chemoenzymatic synthesis by Chi-Huey Wong [80] and Michio Kurosu [81], Wong et al. also synthesized the vancomycin-resistant UDP-MurNAc-L-Ala-y-D-Glu-L-Lys-D-Ala-D-Lac... 

Polyoxins such as polyoxin A, B and D which block the biosynthesis of chitin are competitive inhibitors of uridine diphosphate-N-acetylglucosamine [65]. In resistant isolates of Altemaria kikuchiana, no uptake of dipeptides was observed suggesting that altered dipeptide permease may be responsible for polyoxin resistance [65]. 

The distinction between facilitated diffusion through channels and carrier-mediated transport is somewhat artificial/ but may be justified on the basis of specificity. For example/ 3-lactams in general can pass through nonselective bacterial outer membrane porin (e.g./ OmpF) channels via passive diffusion/ whereas imipenem (and related zwitterionic carbapenems) can also utilize OprD channels/ which preferentially recognize basic amino acids and dipeptides. The identification of mutants that selectively confer imipenem resistance suggests that more intimate protein-drug associations are involved in carrier-mediated transport than in facilitated diffusion/ which may be limited only by pore diameter. 

The rate constants for the hydrolysis of a series of dipeptides of the type glycyl-X and X-glycine were determined at three different concentrations of H+ ion by Muramatu et al. (1963a,b). Table III lists the rate constants reported by these workers. It is noteworthy that dipeptides which contain carboxyl-terminal valine, leucine, or isoleucine are not as resistant to hydrolysis as those containing these amino acids as amino-terminal residues. Hirohata et al. (1953) and Muramatu et al. (1963a,b) have attempted to estimate the magnitude of steric effects on the basis of the known con-... 

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