Structure and function of a novel class of high mannose-binding proteins with anti-viral or anti-tumor activity

Abstract

The recently discovered high mannose (HM)-binding lectin family in lower organisms such as bacteria, cyanobacteria, and marine algae represents a novel class of anti-viral or anti-tumor compounds. This lectin family shows unique carbohydrate binding properties with exclusive high specificity for HM glycans with core trisaccharide comprising Manα(1-3)Manα(1-6)Man at the D2 arm. At low nanomolar levels, these lectins exhibit potent antiviral activity against HIV and influenza viruses through the recognition of HM glycans on virus spike glycoproteins. In addition, some of these lectins, such as bacterial PFL, show cytotoxicity for various cancer cells at low micromolar levels. Cell surface molecules to which PFL bound were identified as integrin alpha 2 and epidermal growth factor receptor (EGFR) by peptide mass finger printing with MALDI-TOF MS. Upon PFL binding, these molecules were rapidly internalized to cytoplasm. EGFR was time dependently degraded in the presence of PFL, and this process was largely responsible for autophagy. Furthermore, PFL sensitizes cancer cells to the EGFR kinase inhibitor, gefitinib. In vivo experiments showed that intratumoral injection of PFL significantly inhibited the growth of tumors in nude mice. PFL-mediated down regulation of integrin/EGFR ultimately contributed to the inhibition of tumor growth both in vitro and in vivo. Thus, the novel anti-cancer mechanism of PFL suggests that this lectin is potentially useful as an anti-cancer drug or as an adjuvant for other drugs. This class of proteins will likely have beneficial impact as a tool for biochemical and biomedical research because of its unique carbohydrate specificity and various biological activities.