Structural requirements for the biological activity of enterostatin.
A series of enterostatin analogues were tested to investigate the minimal structure required for activity to suppress the intake of high-fat (HF) diets. The dose-response curve to intracerebroventricular (ICV) enterostatin was U-shaped (maximal inhibition at 1 nmol). Removal or modification of the N-terminal valine from enterostatin (Val-Pro-Asp-Pro-Arg) abolished activity, as did C-terminal amidation. The tripeptide (Pro-Asp-Pro) and the cyclo-diketopiperazine cyclo-Asp-Pro retained activity whereas the linear Asp-Pro dipeptide was inactive. In rats adapted to a three-choice macronutrient diet, cyclo-Asp-Pro specifically inhibited fat intake and had near maximal inhibition (50%) at the 0.03 nmol dose. The enterostatin inhibitory effect on fat intake may reside in the cyclo-diketopiperazine molecule, cyclo-Asp-Pro.
Lin
L
L
Pennington Biomedical Research Center, Baton Rouge, LA 70808.
Okada
S
S
York
D A
DA
Bray
G A
GA
D000595:Amino Acid Sequence; D000818:Animals; D002552:Cerebral Ventricles; D003089:Colipases / Q000737:chemistry* / Q000494:pharmacology; D004151:Dipeptides; D004305:Dose-Response Relationship, Drug; D004792:Enzyme Precursors; D007263:Infusions, Parenteral; D008297:Male; D008969:Molecular Sequence Data; D011498:Protein Precursors / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D003089:Colipases; D004151:Dipeptides; D004792:Enzyme Precursors; D011498:Protein Precursors; C070752:aspartyl-proline; C037107:procolipase