Treating autoimmune disorders with venom-derived peptides

Abstract

The effective treatment of autoimmune diseases remains a challenge. Voltage-gated potassium Kv1.3 channels, which are expressed in lymphocytes, are a new therapeutic target for treating autoimmune disease. Consequently, Kv1.3 channel-inhibiting venom-derived peptides are a prospective resource for new drug discovery and clinical application. Area covered: Preclinical and clinical studies have produced a wealth of information on Kv1.3 channel-inhibiting venom-derived peptides, especially from venomous scorpions and sea anemones. This review highlights the advances in screening and design of these peptides with diverse structures and potencies. It focuses on representative strategies for improving peptide selectivity and discusses the preclinical research on those venom-derived peptides as well as their clinical developmental status. Expert opinion: Encouraging results indicate that peptides isolated from the venom of venomous animals are a large resource for discovering immunomodulators that act on Kv1.3 channels. Since the structural diversity of venom-derived peptides determines the variety of their pharmacological activities, the design and optimization of venom-peptides for improved Kv1.3 channel-specificity has been advanced through some representative strategies, such as peptide chemical modification, amino acid residue truncation and binding interface modulation. These advances should further accelerate research, development and the future clinical application of venom-derived peptides selectively targeting Kv1.3 channels.

Bldesin, the first functionally characterized pathogenic fungus defensin with Kv1.3 channel and chymotrypsin inhibitory activities

“…Here, we found Bldesin, a pathogenic fungus‐derived antimicrobial defensin peptide with Kv1.3 channel inhibitory activity. These results from our group and Cammue et al indicated that the interaction between natural defensin peptides from different organisms and human potassium channels might be common, which suggested that natural defensins from different organisms might be an important source for the lead drug discovery targeting human potassium channels …”

“…As shown in Figure D, 1000 nM Bldesin inhibited about 40% Kv1.3 channel currents in our electrophysiological experiment system, in which 100 nM BmKTX inhibited about 80% Kv1.3 channel currents. These results indicated that pathogenic fungus‐derived defensin Bldesin has both antimicrobial and Kv1.3 channel inhibitory activities, suggesting its potential functional roles in the defense of environmental bacteria and the Kv1.3 channel‐associated host immunity …”

Animal protein toxins: origins and therapeutic applications

“…Previous studies found that in the process of T lymphocyte immune response, the voltage-gated potassium channel K V 1.3 together with calcium-activated K + channel (K Ca ) contribute to the membrane potential and calcium signaling in T cells (Shen et al . 2017 ). The up-regulated expression of K V 1.3 in T and B lymphocytes is observed during the development of autoimmune diseases (Wang et al .…”

Scorpion Toxins from Buthus martensii Karsch (BmK) as Potential Therapeutic Agents for Neurological Disorders: State of the Art and Beyond

“…The data show that both BmKTX-D33H and ADWX-1 can effectively inhibit the activation and subsequent proliferation of human and rat CD4 + CCR7-TEM cells and the secretion of cytokines [93,94]. It is similar to the pharmacological properties of ShK-186, an anemone toxin analog that has been used in clinical research as a novel drug for the treatment of autoimmune diseases [95]. In addition, ADWX-1 can selectively inhibit the activation of effector memory T cells by inhibiting Kv1.3, thereby significantly improving the symptoms of experimental autoimmune encephalomyelitis (EAE) in a rat model [84,93].…”