Development and Characterization of the Shortest Anti-Adhesion Peptide Analogue of B49Mod1.

Yuan Lyu,Chioma M Okeoma,Wadie D Mahauad-Fernandez

doi:10.3390/molecules25051188

Abstract

Inhibition of cancer cell adhesion is an effective approach to killing adherent cancer cells. B49 and its analog B49Mod1 peptides, derived from the extracellular domain (ECD) of bone marrow stromal antigen 2 (BST-2), display anti-adhesion activity on breast cancer cells. However, the minimal sequence required for this anti-adhesion activity is unknown. Here, we further characterized the anti-adhesion activity of B49Mod1. We show that the anti-adhesion activity of B49Mod1 may require cysteine-linked disulfide bond and that the peptide is susceptible to proteolytic deactivation. Using structure-activity relationship studies, we identified an 18-Mer sequence (B18) as the minimal peptide sequence mediating the anti-adhesion activity of B49Mod1. Atomistic molecular dynamic (MD) simulations reveal that B18 forms a stable complex with the ECD of BST-2 in aqueous solution. MD simulations further reveal that B18 may cause membrane defects that facilitates peptide translocation across the bilayer. Placement of four B18 chains as a transmembrane bundle results in water channel formation, indicating that B18 may impair membrane integrity and form pores. We hereby identify B18 as the minimal peptide sequence required for the anti-adhesion activity of B49Mod1 and provide atomistic insight into the interaction of B18 with BST-2 and the cell membrane.

Highlights

Peptide-based therapeutics is an emergent field for anti-cancer agents with significant benefits that includes ease of production and flexibility for modification
The mechanism of B49Mod1-mediated blocked of of cell adhesion is not known and is not the focus of this study, it is known that the bone marrow stromal antigen 2 (BST-2) extracellular domain (ECD) contains three cysteine residues that are involved in BST-2 dimerization [12,13,14]
The last cysteine residue at position 91 is indispensable for BST-2-mediated promotion of cancer cell adhesion [29], and B49Mod1 may target the cysteine residues in the ECD of BST-2

Summary

Introduction

Peptide-based therapeutics is an emergent field for anti-cancer agents with significant benefits that includes ease of production and flexibility for modification. Cancer metastasis is a complex process involving dissociation of tumor cells from the primary tumor, invasion of the tumor cells into the surrounding tissue, extravasation from circulation, and seeding/growth in distant organs. The attachment of leukocytes/cancer cells to the endothelium is mediated by several cell adhesion molecules (CAMs) different from those at the site of the primary tumor. Cancer cell adhesion is a biological process that is key to the metastatic cascade [1]. Expression of cell-to-cell and cell-to-matrix adhesion molecules, their regulation (up or down), and activation/deactivation have been linked to cancer cell migration and the metastatic cascade [2]. It is important to identify the modulators of cancer cell adhesion and to develop molecules that can inhibit cell adhesion

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