Solution Phase Synthesis, Characterization, and Biological Screening of β-Peptides

Abstract

In recent years, the significant increase in metabolic disorders like type 2 diabetes and obesity has highlighted the urgent need for new therapeutic approaches. Obesity is a risk for health conditions, including diabetes and cardiovascular diseases. One of the promising approaches in developing anti-obesity drugs involves inhibiting pancreatic lipase (PL), an enzyme essential for the digestion of dietary fats. This study investigates the novel use of short α,β- peptides as potential PL inhibitors. These peptides were synthesized using the solution-phase method and characterized through FT-IR and ¹H-NMR spectroscopy. Since L-Proline is often present in natural anti-lipase peptides, it was incorporated as a β-amino acid in the synthesized peptides to enhance anti-lipase activity and proteolytic stability. Notably, L-α-proline was converted into β-amino acid derivatives using the Arndt-Eistert method, which offers stereo control. The resulting peptides exhibiting significant anti-lipase activity include N18 (93%), N27 (92%), N22 (91%), N19 (90%), and N20 (89%). These peptides represent promising lead compounds for further structural optimization to develop more effective molecules for obesity management. In parallel, the surge in type 2 diabetes has driven the search for novel enzyme inhibitors as therapeutic agents. The α-amylase enzyme inhibition is a potential approach for managing diabetes mellitus. Consequently, another focus of this study was the synthesis of short α, β-mixed peptides through solution-phase for potential anti-diabetic application. The synthesis involved converting Boc-protected α-L-leucine to its β-derivative via the Arndt–Eistert reaction, which preserves stereochemical integrity and prevents racemization. Successfully, three novel short-length peptides were synthesized: N23 (18.51%), N25 (45.22%), and N26 (17.05%). These peptides were characterized by FT-IR and ¹H-NMR analysis. Among the synthesized compounds, one demonstrated the highest α-amylase inhibitory activity at 45.22%, with the others exhibiting inhibitory activities of 18.51 and 17.05%. These findings suggest that the synthesized peptides can serve as lead structures for developing more potent α-amylase inhibitors for diabetes management.