Antimicrobial peptides from scorpion venoms

Abstract

The need for new antimicrobial agents is becoming one of the most urgent requirements in modern medicine. The venoms of many different species are rich sources of biologically active components and various therapeutic agents have been characterized including antimicrobial peptides (AMPs). Due to their potent activity, low resistance rates and unique mode of action, AMPs have recently received much attention. This review focuses on AMPs from the venoms of scorpions and examines all classes of AMPs found to date. It gives details of their biological activities with reference to peptide structure. The review examines the mechanism of action of AMPs and with this information, suggests possible mechanisms of action of less well characterised peptides. Finally, the review examines current and future trends of scorpion AMP research, by discussing recent successes obtained through proteomic and transcriptomic approaches.

Keywords: Infection; Pore forming peptides; Scorpion venom; Therapeutics; Venomics.

Graphical abstract

Fig. 1

Different classes of antimicrobial peptides (∼45) derived from scorpion venoms and relative proportion of each category.

Fig. 2

The mechanism of action of AMP's is postulated to occur in a number of stages (Zasloff, 2002): (1) Electrostatic interaction onto the membrane surface; (2) a peptide threshold concentration is reached before membrane disruption can occur after which a number of models have been proposed. In the Carpet model (Pouny and Shai, 1992), peptides remain parallel to the bilayer causing a detergent like effect. In the Barrel stave pore model peptides insert perpendicularly into the bilayer and self-association occurs forming a pore containing peptide–peptide interactions (Baumann and Mueller, 1974). The more recent Toroidal model (Ludtke et al., 1996) indicates a pore forming mechanism in which the pore lumen is lined with both peptides and phospholipid in a less rigid association.

Fig. 3

Pandinin 2 interaction causes negative membrane curvature and insertion of the peptide at a 45°angle (A) Electrostatic attraction of the inner leaflet allows negative membrane curvature and formation of a trans membrane helices (B). Oligomerisation of the peptide occurs within the membrane allowing formation of the barrel stave pore. The pores are further attracted to each other (C), causing pinching off of the membrane between pores (D) This mechanism causes a twofold attack; loss of membrane through pore attraction and loss of intracellular contents through the pores.

Fig. 4

Interaction of Pandinin 1 interaction with phospholipid head groups. Pin1 sits between the head groups (A) within the interface between the head groups and HC core (B). Interactions between pin1 1–18 (green) and the head groups causes negative membrane curvature (A) as pin1 1–18 is at a 30° tilt with respect to pin1 20–44 (red) due to the presence of a proline at position 19. Membrane disruption accrues when pin1 1–18 rotates around the average helical axis, which is parallel to the lipid long axis (C) causing membrane disruption and dispersion of the lipid into the cubic phase (D). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 5

Surface charge distribution (A) and helical wheel projections (B) of the linear antimicrobial peptides meucin-24 and magainin 2 (Gao et al., 2010).

Fig. 6

Helical wheel comparison of IsCT and IsCT2, two short cytolytic peptides from the venom of Opisthanthus madagascarienis.

Fig. 7

Comparison between NMR structures of meucin-13 and meucin-18 (Gao et al., 2009).

Fig. 8

Cecropin A from Hyalophora cecropia, residues highlighted in yellow (A) show the helical regions deduced by NMR. (B) Alignment of the N-terminal regions of 4 scorpine like peptides with Cecropin A. High conservation is seen within areas of the scorpine peptides supporting suggestions made by Zhu and Tytgat, (2004) that the N-terminal region is responsible for the antimicrobial properties of these peptides. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 9

Pandinin 1 from Pandinus imperator-residues highlighted in yellow (A) show the helical regions deduced by NMR. (B) Alignment of the di-helical long chain peptides with Pandinin 1. High conservation is seen within areas of the N-terminal helices (red box) and the hinge region grey box) shown to be critical for function in Pandinin 1 suggesting a shared mechanism of action in this class of peptides. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 10

Helical wheel projections of six short chain cytolytic peptides; each peptide exhibits clear amphipathicity with the amidated C-terminal residue laying within the hydrophobic region creating a ‘polar pocket’ that is essential for the interfacial model. Thus this key amidation site is key for the cytolytic mechanism of short chain peptides from scorpions.

Fig. 11

Helical wheel projections of 4 longer chain short cytolytic peptides; each peptide exhibits clear amphipathicity with the amidated C-terminal residue lying within the hydrophilic region. Thus no polar pocket is present which indicates a mechanism of action different from the interfacial model.

Fig. 12

(A) Pandinin 2 from Pandinus imperator-residues highlighted in yellow show the helical regions deduced by NMR. Residues within the red box thought to be critical for function. (B) Alignment of the 4 mid chain helical peptides with Pandinin 2. (C) Alignment of the four peptides with the GALK motif removed from Pandinin 2 showing a high degree of conservation with the LIPS motif conserved throughout the 4 peptides except in ctriporin where LIPG is seen (red box). (D) Alignment of Pandinin 2 with meucin-18, again a high degree of conservation is seen throughout the peptide with a conservative substitution within the LIPS motif to IIPS. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)