ABSTRACT
Proteins and peptides in mammals are based exclusively on L-amino acids. Recent investigations show that D-amino acids exhibit physiological effects in vivo, despite of their very small quantities. We have investigated the hepatoprotective effects of the Land D-enantiomers of alpha-melanocortin peptide (alpha-MSH). The results showed that peptide-enantiomerism is related to the protective effects of melanocortin peptides in vivo. L-alpha-MSH exhibited potent hepatoprotective effect in the experimental model of acetaminophen induced hepatotoxicity in male CBA mice, while its D-mirror image was inefficient. Furthermore, the antibody to the L-peptide did not recognize the D-structure. The results indicate that the opposite peptide configuration may be used to modulate its function and metabolism in vivo and in vitro.
Subject(s)
Acetaminophen/toxicity , Liver/drug effects , Melanocortins/pharmacology , Animals , Circular Dichroism , Melanocortins/chemistry , Mice , Mice, Inbred CBA , StereoisomerismABSTRACT
Molecular Recognition Theory is based on the finding of Blalock et al. (Biochem. Biophys. Res. Commun. 121 (1984) 203-207; Nature Med. 1 (1995) 876-878; Biochem. J. 234 (1986) 679-683) that peptides specified by the complementary RNAs bind to each other with higher specificity and efficacy. This theory is investigated considering the interaction of the sense peptides coded by means of messenger RNA (read in 5'-->3' direction) and antisense peptides coded in 3'-->5' direction. We analysed the hydropathy of the complementary amino acid pairs and their frequencies in 10 peptide-receptor systems with verified ligand-receptor interaction. An optimization procedure aimed to reduce the number of possible antisense peptides derived from the sense peptide has been proposed. Molecular Recognition Theory was also validated by an "in vivo" experiment. It was shown that 3'-->5', peptide antisense of alpha-MSH abolished its cytoprotective effects on the gastric mucosa in rats. Molecular Recognition Theory could be useful method to simplify experimental procedures, reduce the costs of the peptide synthesis, and improve peptide structure modelling.
