Bouganin, an Attractive Weapon for Immunotoxins

Abstract

Bougainvillea (Bougainvillea spectabilis Willd.) is a plant widely used in folk medicine and many extracts from different tissues of this plant have been employed against several pathologies. The observation that leaf extracts of Bougainvillea possess antiviral properties led to the purification and characterization of a protein, named bouganin, which exhibits typical characteristics of type 1 ribosome-inactivating proteins (RIPs). Beyond that, bouganin has some peculiarities, such as a higher activity on DNA with respect to ribosomal RNA, low systemic toxicity, and immunological properties quite different than other RIPs. The sequencing of bouganin and the knowledge of its three-dimensional structure allowed to obtain a not immunogenic mutant of bouganin. These features make bouganin a very attractive tool as a component of immunotoxins (ITs), chimeric proteins obtained by linking a toxin to a carrier molecule. Bouganin-containing ITs showed very promising results in the experimental treatment of both hematological and solid tumors, and one bouganin-containing IT has entered Phase I clinical trial. In this review, we summarize the milestones of the research on bouganin such as bouganin chemico-physical characteristics, the structural properties and de-immunization studies. In addition, the in vitro and in vivo results obtained with bouganin-containing ITs are summarized.

Keywords: Bougainvillea; VB6-845; antiviral activity; bouganin; cancer therapy; immunotherapy; immunotoxins; rRNA N-glycosylase activity; ribosome-inactivating proteins.

Figure 1

Activity ratio of bouganin compared to other type 1 RIPs and ricin A chain. The bar values represent the ratio between the activity on hsDNA and the activity on cell-free protein synthesis, expressed as 10³ U/mg, as reported in Table 1.

Figure 2

(a) Ribbon model of the crystal structure of bouganin (accession number Protein Data Bank 3CTK). The N-terminal and the C-terminal domains are colored in red and green respectively; (b) Catalytic site of bouganin. The conserved important residues are showed in ball-and-sticks; (c) Structural comparison between different type 1 RIPs and ricin A chain. Superimposition of the Cα atoms of bouganin (magenta), dianthin 30 (green), PAP-R (red) and ricin A chain (gold). The figures were produced by MOLSCRIPT [33] and rendered by RASTER3D [34]; (d) Electrostatic surface potential of bouganin surface at pH 7. The positive regions are represented in blue and the negative ones are colored in red. The active pocket is highlighted by a green circle. The figure was produced by GRASP [35].