Page 14 - Y. Vascular biology

[Y. Vascular biology-8]

N-Terminal modification of the tetrapeptide RLYE, a VEGFR-2

antagonist, improves anti-tumor activity by increasing its

stability against serum peptidases

Taesam Kim¹˙#, Wonjin Park¹˙#, Minsik Kim¹˙#, Suji Kim¹˙²˙#, Young-Guen Kwon³˙#, Young-Myeong Kim¹˙²˙*

¹Molecular and Cellular Biochemistry, Kangwon National University, Chuncheon 200-702, South Korea, ²Institute of

Inclusive Technology, Kangwon National University, Chuncheon 24341, South Korea, ³College of Life Science and
Biotechnology, Yonsei University, Seoul 120-752, South Korea

The tetrapeptide Arg-Leu-Tyr-Glu (RLYE), a vascular endothelial growth factor (VEGF) receptor-2 antagonist, has been

used previously either alone or in combination with chemotherapeutic drugs for treating colorectal cancer in a
mouse model. We analyzed the half-life of the peptide and found that due to degradation by aminopeptidases B

and N, it had a short half-life of 1.2 h in the serum. Therefore, to increase the stability and potency of the peptide,
we designed the modified peptide, N-terminally acetylated RLYE (Ac-RLYE), which had a strongly stabilized half-life

of 8.8 h in serum compared with the original parent peptide. The IC50 value of Ac-RLYE for VEGF-A-induced
endothelial cell migration decreased to approximately 37.1 pM from 89.1 pM for the parent peptide. Using a mouse

xenograft tumor model, we demonstrated that Ac-RLYE was more potent than RLYE in inhibiting tumor angiogenesis
and growth, improving vascular integrity and normalization through enhanced endothelial cell junctions and pericyte

coverage of the tumor vasculature, and impeding the infiltration of macrophages into tumor and their polarization
to the M2 phenotype.