Studies on the Design and Synthesis of Marine Peptide Analogues and Their Ability to Promote Proliferation in HUVECs and Zebrafish

Abstract

In our previous studies, tripeptide 1 was found to induce angiogenesis in zebrafish embryos and in HUVECs. Based on the lead compound 1, seven new marine tripeptide analogues 2–8 have been designed and synthesized in this paper to evaluate the effects on promoting cellular proliferation in human endothelial cells (HUVECs) and zebrafish. Among them, compounds 5–7 possessed more remarkable increasing proliferation effects than other compounds, and the EC50 values of these and the leading compound 1 were 1.0 ± 0.002 μM, 1.0 ± 0.0005 μM, 0.88 ± 0.0972 μM, and 1.31 ± 0.0926 μM, respectively. Furthermore, 5–7 could enhance migrations (58.5%, 80.66% and 60.71% increment after culturing 48 h, respectively) and invasions (49.08%, 47.24% and 56.24% increase, respectively) in HUVECs compared with the vehicle control. The results revealed that the tripeptide including l-Tyrosine or d-Proline fragments instead of l-Alanine of leading compound 1 would contribute to HUVECs’ proliferation. Taking the place of the original (l-Lys-l-Ala) segment of leading compound 1, a new fragment (l-Arg-d-Val) expressed higher performance in bioactivity in HUVECs. In addition, compound 7 could promote angiogenesis in zebrafish assay and it was more interesting that it also could repair damaged blood vessels in PTK787-induced zebrafish at a low concentration. The above data indicate that these peptides have potential implications for further evaluation in cytothesis studies.

Keywords

• marine peptides
• proliferation
• migration
• angiogenesis
• zebrafish