Surfactin variants for intra-intestinal delivery of insulin.

Surfactin is a Bacillus-produced natural lipopeptide, which can overcome the epithelial cell barriers for orally delivering insulin, but its ability to promote uptake of insulin by the intestine need to be further improved for a higher oral bioavailability. Here, we designed and synthesized several surfactin variants to improve its ability for oral delivery of insulin. Firstly, we replaced Glu with Gln in surfactin for decreasing its negative charges, but found this replacement weakened its ability to orally delivery insulin. We further chemically synthesized surfactin variant by replacing its fatty acid chain (C15) with a shortened one (C14), and found this replacement did not influence its ability to orally deliver insulin. Lastly, we replaced its amino acids (Leu) with more hydrophobic ones (Ile), and found the replacement could significantly improve its ability to deliver insulin, with a maximal blood glucose decrease to 27.33% of the initial level and an insulin bioavailability of 18.25%. We also replaced its amino acids of Leu with Val, and Val with Ile, and found this replacement could also significantly improve its ability to deliver insulin with a maximal blood glucose decrease to 18.36% of the initial level and a high insulin bioavailability of 26.32% in diabetic mice. Further analysis by CD, we found the surfactin variants with more hydrophobic amino acid residuals significantly induced insulin from rigid (α-helix) to flexible structure (β-sheet and random coil), that is favorable for insulin to permeate across the intestine epithelial membrane. Collectively, surfactin variants with more hydrophobicity are very potential for delivery of insulin in the everyday control of blood glucose.