Peptide name : Piscidin 3

Source/Organism : Morone chrysops x Morone saxatilis

Linear/Cyclic : Linear

Chirality : L

Peptide length: 22

C-terminal modification: Linear

N-terminal modification : Free

Non-natural peptide information: Cu2+ bound

Assay type : MTT assay

Assay time : 24-h

Activity : IC50 = 5.52 µM

Cell line : HT-1080

Cancer type : Fibrosarcoma

Other activity : Anticancer

Amino acid composition bar chart :

Molecular mass : 2491.895 Dalton

Aliphatic index : 1.063

Instability index : 39.6636

Hydrophobicity (GRAVY) : 0.4545

Isoelectric point : 12

Charge (pH 7) : 3.0216

Aromaticity : 13.63

Molar extinction coefficient (cysteine, cystine): (0, 0)

Hydrophobic/hydrophilic ratio : 1.75

hydrophobic moment : 0.6072

Missing amino acid : C,D,E,K,M,N,P,Q,W,Y

Most occurring amino acid : I

Most occurring amino acid frequency : 4

Least occurring amino acid : V

Least occurring amino acid frequency : 1

Secondary structure fraction (Helix, Turn, Sheet): (9.0, 22., 45.)

SMILES Notation: CC[C@H](C)[C@H](NC(=O)CNC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccccc1)[C@@H](C)CC)[C@@H](C)CC)C(=O)N[C@H](C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)NCC(=O)O)[C@@H](C)O)[C@@H](C)CC)C(C)C

1 : Comert F, et al. Copper-binding anticancer peptides from the piscidin family: an expanded mechanism that encompasses physical and chemical bilayer disruption. Sci Rep. 2021; 11:12620. doi: 10.1038/s41598-021-91670-w

Paper title : Copper-binding anticancer peptides from the piscidin family: an expanded mechanism that encompasses physical and chemical bilayer disruption.

Doi : https://doi.org/10.1038/s41598-021-91670-w

Abstract : In the search for novel broad-spectrum therapeutics to fight chronic infections, inflammation, and cancer, host defense peptides (HDPs) have garnered increasing interest. Characterizing their biologically-active conformations and minimum motifs for function represents a requisite step to developing them into efficacious and safe therapeutics. Here, we demonstrate that metallating HDPs with Cu2+ is an effective chemical strategy to improve their cytotoxicity on cancer cells. Mechanistically, we find that prepared as Cu2+-complexes, the peptides not only physically but also chemically damage lipid membranes. Our testing ground features piscidins 1 and 3 (P1/3), two amphipathic, histidine-rich, membrane-interacting, and cell-penetrating HDPs that are α-helical bound to membranes. To investigate their membrane location, permeabilization effects, and lipid-oxidation capability, we employ neutron reflectometry, impedance spectroscopy, neutron diffraction, and UV spectroscopy. While P1-apo is more potent than P3-apo, metallation boosts their cytotoxicities by up to two- and seven-fold, respectively. Remarkably, P3-Cu2+ is particularly effective at inserting in bilayers, causing water crevices in the hydrocarbon region and placing Cu2+ near the double bonds of the acyl chains, as needed to oxidize them. This study points at a new paradigm where complexing HDPs with Cu2+ to expand their mechanistic reach could be explored to design more potent peptide-based anticancer therapeutics.