Further Structural Optimization and SAR Study of Sungsanpin Derivatives as Cell Invasion Inhibitors

Abstract

Cancer metastasis is one of the major causes of mortality in patients with cancer, and cell invasion plays a fundamental role in this process. Because of the absence of effective treatments, managing these patients is challenging. Recently, we optimized the structure of the natural peptide lasso Sungsanpin and identified two peptides: octapeptide S3 and cyclic peptide S4, which inhibited the invasion of A549 cells effectively. In this work, we performed an alanine scan of S3 to explore the structure-activity relationship and found linear octapeptide S3-4 and cyclic peptide S4-1 that exhibited improved inhibition of invasion on A549 cells. Then we further modified S3-4 and resulted in S3-11, which displayed much higher inhibitory activity in the cell invasion assay against A549 cell line than S3-4. Of all peptides, S4-1 significantly upregulated TIMP-1 and TIMP-2 mRNA level.

Note:
Funding declaration: This work was supported by the National Natural Science Foundation of China (No. 82204347, to CG) and Naval Medical University Young Research Fellowship Grant (2021QN12).

Conflict of Interests: The authors declare no conflict of interest.

Keywords: peptide drug design, Structure-activity relationship, cancer invasion, MMP, TIMP-1/TIMP-2