Anticancer α-Helical Peptides and Structure / Function Relationships Underpinning Their Interactions with Tumour Cell Membranes

Abstract

Cancer is a major cause of premature death and there is an urgent need for new anticancer agents with novel mechanisms of action. Here we review recent studies on a group of peptides that show much promise in this regard, exemplified by arthropod cecropins and amphibian magainins and aureins. These molecules are alpha-helical defence peptides, which show potent anticancer activity (alpha-ACPs) in addition to their established roles as antimicrobial factors and modulators of innate immune systems. Generally, alpha-ACPs exhibit selectivity for cancer and microbial cells primarily due to their elevated levels of negative membrane surface charge as compared to non-cancerous eukaryotic cells. The anticancer activity of alpha-ACPs normally occurs at micromolar levels but is not accompanied by significant levels of haemolysis or toxicity to other mammalian cells. Structure/function studies have established that architectural features of alpha-ACPs such as amphiphilicty levels and hydrophobic arc size are of major importance to the ability of these peptides to invade cancer cell membranes. In the vast majority of cases the mechanisms underlying such killing involves disruption of mitochondrial membrane integrity and/or that of the plasma membrane of the target tumour cells. Moreover, these mechanisms do not appear to proceed via receptor-mediated routes but are thought to be effected in most cases by the carpet/toroidal pore model and variants. Usually, these membrane interactions lead to loss of membrane integrity and cell death utilising apoptic and necrotic pathways. It is concluded that that alpha-ACPs are major contenders in the search for new anticancer drugs, underlined by the fact that a number of these peptides have been patented in this capacity.

Antitumor activity of a membrane lytic peptide cyclized with a linker sensitive to membrane type 1-matrix metalloproteinase

“…S2). 5 The major cleavage site was as expected and shown in Table 1. We differentiated the cyclized and linear form by their difference in elution time over the reverse-phase HPLC column.…”

“…S1). 5 L-18, D-18, and H-18 are stereoisomers of identical amino acid composition and sequence: the former two are of opposite chirality to each other, whereas H-18 is a hybrid sequence with five residues randomly replaced by the corresponding D-amino acids. cycL-25 is a 25-residue sequence composed of a segment preferentially cleavable by MT1-MMP (27) and a membrane lytic segment identical to L-18.…”

“…As shown in Supplementary Fig. S2, 5 intact and cleaved cycL-25 eluted at 20.6 and 20.9 min, respectively. The cleavage was further confirmed by mass spectrometry analysis of the eluted fractions ( Supplementary Fig.…”

“…S4). 5 When peptides were transferred to SDS, a membrane-mimicking solution, highly helical structures were observed for L-18, D-18, and reduced cycL-25 but not for H-18 and intact cycL-25. The hybrid peptide H-18 did not show any significant helical structure in either an aqueous or membrane-mimicking environment.…”

“…S3). 5 After 1 h incubation with MT1-MMP, 52% peptides were converted to linear form. This number increase to 82% in 5 h. Some minor peaks were observed after 2 h of incubation, indicating the presence of side reactions.…”