Pentapeptide analogues

LY 127623 BCW59-A) is a synthetic pentapeptide analogue of enkephalin, and is an opioid RECEPTOR agonist with OPIOID analgesic activity. 

Nozawa, T., Tamai, I., Sai, Y., Nezu, J. and Tsuji, A. (2003) Contribution of organic anion transporting polypeptide OATP-C to hepatic elimination of the opioid pentapeptide analogue [D-Ala2, D-Leu5]-enkephalin. The Journal of Pharmacy and Pharmacology, 55, 1013-1020. 

The intramolecular long-range acyl migration via 13-, 15-, and 16-membered cyclic transition states to form tetra- and pentapeptide analogues has been reported for S-acylcysteine peptides containing 0- or y-amino acids (Scheme 82). ... 

There have been a number of hypotheses regarding the mode of action of /8-lactam antibiotics [237,238]. That most widely used at present is the structural analogue hypothesis [183,215], based on the structural similarity between penicillins and a possible conformation of the acyl-D-alanyl-D-alanine end of the N-acetylmuramyl-pentapeptide strand of the bacterial cell wall. A number of experimental data support this hypothesis (for recent reviews see [237] and [238]) and the model attractively explains the mechanism of action of /3-lactam antibiotics, especially penicillins. Nevertheless, certain more recent data contradict the structural analogue model [239-241] and a conformational response model has been set up [242,243]. It must be emphasized, however, that the contradictions are sometimes only apparent, and a one-sided interpretation of the structure-activity data may lead to false conclusions, e.g. the problem of the 6(7)a-substitution in penicillins and cephalosporins. 

The role of /3-lactam antibiotics in these reactions has been pointed out by several workers [183,215,252-255], and supported by many experimental data. It was assumed that the structural similarity between penicillins and the terminal acyl-D-Ala-D-Ala moiety of the pentapeptide chain plays an important role [183], as exemplified by the Dreiding stereomodels of acyl-D-Ala-D-Ala and a 6a-methylpenicillin shown in Figure 8.5. This structural similarity is not so close in 3-cephems as in penicillins, but 2-cephems, although practically inactive derivatives as antibiotics [41,79], are better structural analogues of acyl-D-Ala-D-Ala. 

The interactions of 8-lactams with PBPs indicate that these compounds are structural analogues of R-D-alanyl-D-alanine, the natural substrate of peptidoglycan transpeptidases and D-alanine carboxypeptidases, where R is the remainder of the pentapeptide. The mechanisms of the transpeptidase and carboxypeptidase reactions are thought to involve formation of an acyl-enzyme intermediate that can react with either a primary amine (e.g., an a-amino group) to form a peptide bond, or with water to form a carboxylic acid. In both reactions D-alanine is released before the acyl enzyme is formed. When a S-lactam antibiotic enters the binding site, the /1-lactam bond is hydrolyzed, and the resulting acyl group reacts with the active-site... 

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