Insights into the molecular basis underlying cancer cell sensitivity to Polybia MP1 peptides

During the past few decades, research has focused on antimicrobial peptides
(AMPs) having a dual nature; they not only have bactericidal properties but may also
target cancer cells. It has been proven that the mechanism of cationic AMPs is initiated
by their electrostatic interaction with negatively charged membrane lipids. Of note,
tumour cell lipid composition differs from the non-transformed cell profile.
Therefore, AMPs seem to be prospective candidates to target cancer cells.
This project aimed at elucidating the structure-function relationship of the peptide
Polybia-MP1 in its anticancer activity. MP1 mechanism of action underwent detailed
mechanistic characterisation by applying rationally designed MP1 derivatives in
systems of increasing complexity using biophysical and biological approaches. The
presented work provides insights into the molecular basis underlying cell sensitivity
to MP1. Chemical modifications of native structure allowed for determining amino
acid residues important in MP1 activity and for identifying derivatives that displayed
greater potency against cancer-like systems Testing the peptide library emphasized the
interplay between charge modification, physiochemical characteristics of each residue
and hydrophilic: hydrophobic face arrangement in modulating potency and specificity.
GPMV formation, live cell-derived membrane platforms, although challenging and
requiring optimization, facilitated studies of lipid organization indicating that variable
lipid packing is a molecular determinant modulating MP1 phenomenon. Despite in
silico transcriptomic analysis identifying prospective gene targets that might be
influencing cell sensitivity to MP1, further cell viability testing failed to uncover
potential molecular mechanisms. This work provides a novel insight into the role of
lipid packing in the membranolytic activity of MP1 and paves new directions in the
structure-function exploration of MP1.