The Aromatic Head Group of Spider Toxin Polyamines Influences Toxicity to Cancer Cells.

David Wilson,Michael Liddell,Matthew Nolan,Alex Loukas,Lachlan Rash,Glen Boyle,Lachlan Mcintyre,Leon Tribolet,Jennifer Smith,Peter Parsons,Norelle Daly

doi:10.3390/toxins9110346

Abstract

Spider venoms constitute incredibly diverse libraries of compounds, many of which are involved in prey capture and defence. Polyamines are often prevalent in the venom and target ionotropic glutamate receptors. Here we show that a novel spider polyamine, PA366, containing a hydroxyphenyl-based structure is present in the venom of several species of tarantula, and has selective toxicity against MCF-7 breast cancer cells. By contrast, a polyamine from an Australian funnel-web spider venom, which contains an identical polyamine tail to PA366 but an indole-based head-group, is only cytotoxic at high concentrations. Our results suggest that the ring structure plays a role in the cytotoxicity and that modification to the polyamine head group might lead to more potent and selective compounds with potential as novel cancer treatments.

Highlights

The discovery of new compounds from nature is still one of the most efficient methods for finding lead molecules for the development of pharmaceuticals [1,2]
The two polyamines consist of a spermine tail functionalised with an aromatic head group, and are identical except
PA389 only displays cytotoxicity at high concentrations in contrast to PA366, indicating that the aromatic head group is important for cytotoxicity

Summary

Introduction

The discovery of new compounds from nature is still one of the most efficient methods for finding lead molecules for the development of pharmaceuticals [1,2]. These new compounds range from small molecules to large biologics, and several approaches have facilitated their discovery. NMR spectroscopy and recent advances in metabolomics have been valuable for characterising novel small molecules, whereas advances in genomics and proteomics, as well as high-throughput screening approaches are providing novel methods for the discovery of peptides and proteins [3,4]. Spider venoms have enormous compound diversity, much of which has yet to be explored. More than four million compounds are estimated to be present in the venom of the 46,000 different spider species [5,6]

Methods

Results

Conclusion