Ahmed_2024_Molecules_29_

Obesity is a source of significant pathologies and deadly diseases, including heart disease, diabetes, and cancer. One of the most intriguing strategies in the hunt for new anti-obesity medications is the inhibition of pancreatic lipase (PL). This study presents a novel application of short alpha and beta-mixed peptides as pancreatic lipase inhibitors. These peptides were synthesized in the solution phase and characterized using FTIR and (1)H-NMR. L-proline is present in a high percentage of natural anti-lipase peptides and was used as a beta-amino acid in this study to enhance anti-lipase activity and proteolytic stability. Moreover, L-alpha-proline was converted to beta-amino acid derivatives using the Arndt-Eistert method with the advantage of stereo control at the alpha-carbon. The synthesized peptides with anti-lipase activity are N-Boc-beta-Pro-Gly-OBz (93%), N-Boc-O-Bz-Tyr-beta-Pro-beta-Pro-Gly-OBz (92%), N-Boc-O-Bz-Tyr-beta-Pro-COOH (91%), N-Boc-Phe-beta-Pro-OCH(3) (90%), and N-Boc-O-Bz-Tyr-beta-Pro-OCH(3) (89%). These peptides may function as lead molecules for further modification to more significant molecules, which can help control obesity.