The Spectrum of Design Solutions for Improving the Activity-Selectivity Product of Peptide Antibiotics against Multidrug-Resistant Bacteria and Prostate Cancer PC-3 Cells

Abstract

The link between the antimicrobial and anticancer activity of peptides has long been studied, and the number of peptides identified with both activities has recently increased considerably. In this work, we hypothesized that designed peptides with a wide spectrum of selective antimicrobial activity will also have anticancer activity, and tested this hypothesis with newly designed peptides. The spectrum of peptides, used as partial or full design templates, ranged from cell-penetrating peptides and putative bacteriocin to those from the simplest animals (placozoans) and the Chordata phylum (anurans). We applied custom computational tools to predict amino acid substitutions, conferring the increased product of bacteriostatic activity and selectivity. Experiments confirmed that better overall performance was achieved with respect to that of initial templates. Nine of our synthesized helical peptides had excellent bactericidal activity against both standard and multidrug-resistant bacteria. These peptides were then compared to a known anticancer peptide polybia-MP1, for their ability to kill prostate cancer cells and dermal primary fibroblasts. The therapeutic index was higher for seven of our peptides, and anticancer activity stronger for all of them. In conclusion, the peptides that we designed for selective antimicrobial activity also have promising potential for anticancer applications.

Designed Multifunctional Peptides for Intracellular Targets

“…The expression of homeobox-containing proteins has been confirmed in Trichoplax adhaerens and other placozoans [ 81 , 82 , 83 ]. T. adhaerens express genes encoding for proteins implicated in morphogenesis [ 84 ], innate immunity [ 85 , 86 , 87 , 88 , 89 , 90 ], and motility [ 91 ]. Moving and sensing are possible without brain cells but not without specialized proteins.…”

“…In our experience, the majority of natural or designed peptide antibiotics with an excellent performance against a broad spectrum of Gram-negative and Gram-positive bacteria (including some multidrug clinical isolates) are likely to exhibit some degree of selective anticancer activity too. Good examples are the peptides we designed and named trichoplaxin-2a, pexiganan-L18, flexampin, zyk-1, adepantin-1a, and mapegin [ 88 ]. Their respective sequences are: RHHWRRYARIGFRAVRTVIGK (T2R1), GIGKFLKKAKKFGKAFVLILKK (PEXA), GIKKWVKGVAKGVAKDLAKKIL (FLEX), GIGREIIKKIIKKIGKKIGRII (ZYK1), GIKKAVGKALKGLKGLLKALGES (A1A), and KIGKKILKALKGALKELA (MAPA).…”

“…Their respective sequences are: RHHWRRYARIGFRAVRTVIGK (T2R1), GIGKFLKKAKKFGKAFVLILKK (PEXA), GIKKWVKGVAKGVAKDLAKKIL (FLEX), GIGREIIKKIIKKIGKKIGRII (ZYK1), GIKKAVGKALKGLKGLLKALGES (A1A), and KIGKKILKALKGALKELA (MAPA). For prostate cancer PC-3 cells, the IC50 concentrations ranged from 1.5 (Zyk-1) to 12 μM (A1A), which is 40 to 5 times stronger anticancer activity compared to the Polybia-MP1 anticancer peptide IDWKKLLDAAKQIL-NH2 [ 88 , 294 ].…”

“…It can also begin with known CPP by introducing amino acid substitutions to widen its activity spectrum. Let us first describe how we achieved the goal of in vitro antibacterial and anticancer activity for a modified CPP named mapegin [ 88 ]. Its parent CPP is well-known MAP sequence KLALKLALKALKAALKLA [ 166 ].…”

“…Its parent CPP is well-known MAP sequence KLALKLALKALKAALKLA [ 166 ]. Rational design by Juretić et al [ 88 ] resulted in the mapegin sequence K IGK K I LKALK G ALK E LA (named MAPA). It differs from the MAP sequence in highlighted and underlined amino acid residues I2, G3, K4, I6, G12, and E16, which increased flexibility (due to two glycines) but did not decrease the high amphipathicity feature of the parent peptide.…”