An integrated biophysics approach towards realisation of a new class of membrane-active anticancer therapies

点击翻译按钮获取中文摘要

Organisms are well known to produce their own antibiotic host-defence peptides that act through damaging bacterial membranes due to their different molecular composition compared to the host organism's own cells. Some of these antimicrobial peptides are also known to have anticancer properties. One particularly promising anticancer peptide is polybia MP1 (MP1) from the venom of the Brazilian wasp Paulista Polybia.The mechanistic basis for the anticancer properties of these peptides bears similarities to their antimicrobial mode of action. Recently we showed that MP1's membrane disrupting effects were significantly amplified by two classes of lipid, PE and PS, which are present in much higher composition on the surface of cancer cells than the cells of normal tissue. Therefore, MP1 is a promising candidate peptide for development of a novel anticancer agent. This project will aim to optimise this peptide for potency and specificity to generate promising compounds for further clinical development.Through our current understanding of its interaction mechanism and how this relates to molecular structure, we will generate a set of MP1-derived peptides with predetermined single changes in amino acid composition. These peptides will be screened for activity against model membranes with compositions representative of cancer and normal cells as well as cancer and normal cell lines. Mutations that display enhanced potency or specificity compared to MP1 will be combined in a second round of designed peptides and activity screening. The most promising peptides from this screening phase will be taken forward for more detailed characterisation of their interactions with membranes and cells. We will use a novel approach that takes advantage of the different insights we can gain from systems of increasing complexity from minimal membrane models with simplified lipid mixtures representative of key compositional contents of the relevant cells, to membranes extracted from the relevant cells, to the cells themselves. This will allow unprecedented correlation between the detailed biophysical information obtained from model membranes to the complex biological response in whole cells. The lipid compositions of the cell lines will also be characterised, with particular interest in the compositions of membranes that are most sensitive to and those that are most resistant to peptide-induced membrane disruption.Application of highly sensitive surface analytical and optical microscopy techniques will provide detailed insight into the nature of peptide-membrane interactions. Importantly, beyond development of an anticancer peptide, this information will contribute valuable fundamental insight into the relationship between peptide structure, membrane composition and interaction mechanism that will be of use in the development of a wide range of membrane-active peptides, including antimicrobial peptides and cell penetrating peptides.We aim to identify the three most potent compounds that can be taken forward towards first-in-man clinical trials through full preclinical development in a project that will follow on from this one. No current anticancer drug targets the membrane of these cells. Therefore successful translation of an MP1-derived peptide would signal a new class of anticancer drug in the therapeutic arsenal against cancer. In particular we will also test the peptides' promise for use in combination with existing chemotherapeutics and investigate any synergistic effects.