Short Peptides from Asian Scorpions: Bioactive Molecules with Promising Therapeutic Potential

Abstract

Scorpion venom peptides, particularly those derived from Asian species, have garnered significant attention, offering therapeutic potential in pain management, cancer, anticoagulation, and infectious diseases. This review provides a comprehensive analysis of scorpion venom peptides, focusing on their roles as voltage-gated sodium (Nav), potassium (Kv), and calcium (Cav) channel modulators. It analyzed Nav1.7 inhibition for analgesia, Kv1.3 blockade for anticancer activity, and membrane disruption for antimicrobial effects. While the low targeting specificity and high toxicity of some scorpion venom peptides pose challenges to their clinical application, recent research has made strides in overcoming these limitations. This review summarizes the latest progress in scorpion venom peptide research, discussing their mechanisms of action, therapeutic potential, and challenges in clinical translation. This work aims to provide new insights and directions for the development of novel therapeutic drugs.

Keywords: ion channel blocker; membrane-targeting mechanisms; peptide engineering; scorpion venom peptides; therapeutic potential.

Figure 1

Potential targets of scorpion venom peptides in pain management. Scorpion venom peptides exert their analgesic effects primarily by modulating pain-related ion channels, including VGSCs (green), VGPCs (red), VGCCs (blue), TRPs (purple), purinergic P2X ion channels (yellow), and ASICs (orange).

Figure 2

Structural characteristics of VGSCs. (a) In mammals, sodium channels are composed of an α-subunit and one or more β-subunits. The α-subunit consists of four homologous domains: DI (orange), DII (green), DIII (turquoise blue), and DIV (blue). Each domain is made up of six transmembrane segments (S1–S6), where S1–S4 form the voltage-sensing domain and S5–S6 constitute the pore-forming domain. The positively charged amino acid residues on the S4 segment detect changes in membrane potential and regulate the opening of the sodium channel. The intracellular loop between DIII and DIV functions as an inactivation gate, closing the sodium channel during rapid inactivation. The β subunit (yellow) consists of an N-terminal extracellular immunoglobulin (Ig)-like fold, a transmembrane segment, and a short intracellular C-terminus. It is an auxiliary component of the VGSC and does not participate in the formation of the pore. (b) Sodium ion channels exist in three states: the resting state, the activated state, and the inactivated state. When in the activated state, the channel opens, allowing the influx of sodium ions. Abnormal activation of sodium ion channels can lead to the generation of pain responses in the body.

Figure 3

Scorpion venom peptides with analgesic activity and their modes of action. Analgesic scorpion venom peptides targeting sodium channels are divided into three categories: (1) those targeting a single sodium channel, (2) those targeting multiple sodium channels, and (3) those that have not been fully explored. These peptides are further classified into α-toxin (green) and β-toxin (blue), based on distinct action sites on VGSCs and their electrophysiological properties. The scorpion venom peptides that have not yet been clearly classified are represented in gray.