Anionic antimicrobial peptides (AAMPs) have been identified in a wide variety of plant species with net charges that range between −1 and −7 and structures that include: extended conformations, α-helical architecture and cysteine stabilized scaffolds. These peptides commonly exist as multiple isoforms within a given plant and have a range of biological activities including the ability to kill cancer cells as well as phytopathogenic bacteria, fungi, pests, molluscs, and other predatory species. In general, the killing mechanisms underpinning these activities are poorly understood although they appear to involve attack on intracellular targets such as DNA along with compromise of cell envelope integrity through lysis of the cell wall via chitin-binding and/or permeabilisation of the plasma membrane via lipid interaction. It is now becoming clear that AAMPs participate in the innate immune response of plants and make a major contribution to the arsenal of defence toxins produced by these organisms to compensate for their lack of some defence mechanisms possessed by mammals, such as mobility and a somatic adaptive immune system. Based on their biological properties, a number of potential uses for plant AAMPs have been suggested, including therapeutically useful anticancer agents and novel antimicrobial compounds, which could be utilized in a variety of scenarios, ranging from the protection of crops to the disinfection of hospital environments

Development of selective hDM2/X p53 inhibitors is key to further develop this anticancer target. This method displayed a 50% success rate and identified hDMX selective compounds.

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Globally, death due to cancers is likely to rise to over 20 million by 2030, which has created an urgent need for novel approaches to anticancer therapies such as the development of host defence peptides. Cn-AMP2 (TESYFVFSVGM), an anionic host defence peptide from green coconut water of the plant Cocos nucifera, showed anti-proliferative activity against the 1321N1 and U87MG human glioma cell lines with IC50 values of 1.25 and 1.85 mM, respectively. The membrane interactive form of the peptide was found to be an extended conformation, which primarily included β-type structures (levels > 45%) and random coil architecture (levels > 45%). On the basis of these and other data, it is suggested that the short anionic N-terminal sequence (TES) of Cn-AMP2 interacts with positively charged moieties in the cancer cell membrane. Concomitantly, the long hydrophobic C-terminal sequence (YFVFSVGM) of the peptide penetrates the membrane core region, thereby driving the translocation of Cn-AMP2 across the cancer cell membrane to attack intracellular targets and induce anti-proliferative mechanisms. This work is the first to demonstrate that anionic host defence peptides have activity against human glioblastoma, which potentially provides an untapped source of lead compounds for development as novel agents in the treatment of these and other cancers.

Scaffolds have been identified which provide promising platforms for future development of chemotherapeutic agents against resistant glioblastoma subtypes.

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Abstract:It is becoming increasingly clear that plants ranging across the plant kingdom produce anionic host defence peptides (AHDPs) with potent activity against a wide variety of human cancers cells. In general, this activity involves membrane partitioning by AHDPs, which leads to membranolysis and / or internalization to attack intracellular targets such as DNA. Several models have been proposed to describe these events including: the toroidal pore and Shai-Matsuzaki-Huang mechanisms but, in general, the mechanisms underpinning the membrane interactions and anticancer activity of these peptides are poorly understood. Plant AHDPs with anticancer activity can be conveniently discussed with reference to two groups: cyclotides, which possess cyclic molecules stabilized by cysteine knot motifs, and other ADHPs that adopt extended andhelical conformations. Here, we review research into the anticancer action of these two groups of peptides along with current understanding of the mechanisms underpinning this action.

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