Recently proposed casual links and pathological similarities between cancer and infectious diseases suggest potential combined therapeutics. Promising candidates include cationic antimicrobial peptides (CAPs) that form part of the innate immunity armory of most living taxa. These molecules are generally small (<10 kDa), highly basic and exhibit broad-spectrum antimicrobial activity and immunomodulating effects. Although it is generally accepted that CAP-mediated actions are initiated by electrostatic interactions at the plasma membrane (possibly with anionic lipids or other negatively-charged components), precise molecular target(s) and detailed mechanism(s) of downstream events remain unclear.

Using bioinformatic tools, we found striking structural similarities among a number of CAPs, including plant and human defensins, despite little sequence identities. Their structures potentially all comprise dimeric forms with a highly-positively charged “grip” conformation formed by specific basic loops of two monomers. Interestingly, these defensins exhibit specific tumour cell-killing activity, caused by rapid cell permeabilisation associated with membrane blebbing prior to cell lysis. We also found that their tumour cell cytotoxicity correlates with binding to functionally essential phosphoinositides (PIPs), which is likely mediated via the abovementioned structural “grips”. This not only implies evolutionary conservation of CAP structures and functions, but also enables us to explore a new class of PIP-binding CAPs as novel multifunctional therapeutics.