Ion channels play fundamental roles in both excitable and non-excitable tissues and therefore constitute attractive drug targets for myriad neurological, cardiovascular and metabolic diseases as well ...as for cancer and immunomodulation. However, achieving selectivity for specific ion channel subtypes with small-molecule drugs has been challenging, and there currently is a growing trend to target ion channels with biologics. One approach is to improve the pharmacokinetics of existing or novel venom-derived peptides. In parallel, after initial studies with polyclonal antibodies demonstrated the technical feasibility of inhibiting channel function with antibodies, multiple preclinical programmes are now using the full spectrum of available technologies to generate conventional monoclonal and engineered antibodies or nanobodies against extracellular loops of ion channels. After a summary of the current state of ion channel drug discovery, this Review discusses recent developments using the purinergic receptor channel P2X purinoceptor 7 (P2X7), the voltage-gated potassium channel K
1.3 and the voltage-gated sodium channel Na
1.7 as examples of targeting ion channels with biologics.
For more than 25 years, it has been widely appreciated that Ca²⁺ influx is essential to trigger T-lymphocyte activation. Patch clamp analysis, molecular identification, and functional studies using ...blockers and genetic manipulation have shown that a unique contingent of ion channels orchestrates the initiation, intensity, and duration of the Ca²⁺ signal. Five distinct types of ion channels - Kv1.3, KCa3.1, Orai1+ stromal interacting molecule 1 (STIM1) Ca²⁺-release activating Ca²⁺ (CRAC) channel, TRPM7, and Clswell- comprise a network that performs functions vital for ongoing cellular homeostasis and for T-cell activation, offering potential targets for immunomodulation. Most recently, the roles of STIM1 and Orai1 have been revealed in triggering and forming the CRAC channel following T-cell receptor engagement. Kv1.3, KCa3.1, STIM1, and Orai1 have been found to cluster at the immunological synapse following contact with an antigen-presenting cell; we discuss how channels at the synapse might function to modulate local signaling. Immuno-imaging approaches are beginning to shed light on ion channel function in vivo. Importantly, the expression pattern of Ca²⁺ and K⁺ channels and hence the functional network can adapt depending upon the state of differentiation and activation, and this allows for different stages of an immune response to be targeted specifically.
•The Kv1.3 channel in T cells is a validated therapeutic target for autoimmune diseases.•The most potent blockers are peptides from scorpions and sea anemones.•Phase 1 clinical trials with dalazatide ...(ShK-186) show highly promising results.•Buccal and pulmonary administration are suitable for delivering Kv1.3-blocking peptides.•Peptides can be conjugated with larger carriers but this may not be necessary for efficacy in vivo.
The voltage-gated Kv1.3 channel in T lymphocytes is a validated therapeutic target for diverse autoimmune diseases. Here we review the discovery of Kv1.3, its physiological role in T cells, and why it is an attractive target for modulating autoimmune responses. We focus on peptide inhibitors because the first Kv1.3-selective inhibitor in human trials is a peptide derived from a marine organism. Two broad classes of peptides block Kv1.3, the first from scorpions and the second from sea anemones. We describe their structures, their binding site in the external vestibule of Kv1.3, how they have been engineered to improve Kv1.3-specificity, and their pharmacokinetic and pharmacodynamic properties. Finally, we highlight the therapeutic potential of Kv1.3 peptide inhibitors to treat autoimmune diseases without compromising protective immune responses.
Voltage-gated potassium channels play a key role in human physiology and pathology. Reflecting their importance, numerous channelopathies have been characterised that arise from mutations in these ...channels or from autoimmune attack on the channels. Voltage-gated potassium channels are also the target of a broad range of peptide toxins from venomous organisms, including sea anemones, scorpions, spiders, snakes and cone snails; many of these peptides bind to the channels with high potency and selectivity. In this review we describe the various classes of peptide toxins that block these channels and illustrate the broad range of three-dimensional structures that support channel blockade. The therapeutic opportunities afforded by these peptides are also highlighted.
This article is part of the Special Issue entitled ‘Venom-derived Peptides as Pharmacological Tools.’
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•Voltage-gated potassium channels play key roles in human physiology and pathology.•Numerous channelopathies are associated with these channels.•Voltage-gated potassium channels are the target of a wide range of peptide toxins.•These peptide toxins adopt many different three-dimensional structures.•Voltage-gated potassium channels are valuable therapeutic targets.
A subset of potassium channels is regulated primarily by changes in the cytoplasmic concentration of ions, including calcium, sodium, chloride, and protons. The eight members of this subfamily were ...originally all designated as calcium-activated channels. More recent studies have clarified the gating mechanisms for these channels and have documented that not all members are sensitive to calcium. This article describes the molecular relationships between these channels and provides an introduction to their functional properties. It also introduces a new nomenclature that differentiates between calcium- and sodium-activated potassium channels.
We report two structures of the human voltage-gated potassium channel (Kv) Kv1.3 in immune cells alone (apo-Kv1.3) and bound to an immunomodulatory drug called dalazatide (dalazatide-Kv1.3). Both the ...apo-Kv1.3 and dalazatide-Kv1.3 structures are in an activated state based on their depolarized voltage sensor and open inner gate. In apo-Kv1.3, the aromatic residue in the signature sequence (Y447) adopts a position that diverges 11 Å from other K
channels. The outer pore is significantly rearranged, causing widening of the selectivity filter and perturbation of ion binding within the filter. This conformation is stabilized by a network of intrasubunit hydrogen bonds. In dalazatide-Kv1.3, binding of dalazatide to the channel's outer vestibule narrows the selectivity filter, Y447 occupies a position seen in other K
channels, and this conformation is stabilized by a network of intersubunit hydrogen bonds. These remarkable rearrangements in the selectivity filter underlie Kv1.3's transition into the drug-blocked state.
The tumour microenvironment (TME) imposes a major obstacle to infiltrating T-lymphocytes and suppresses their function. Several immune checkpoint proteins that interfere with ligand/receptor ...interactions and impede T-cell anti-tumour responses have been identified. Immunotherapies that block immune checkpoints have revolutionized the treatment paradigm for many patients with advanced-stage tumours. However, metabolic constraints and soluble factors that exist within the TME exacerbate the functional exhaustion of tumour-infiltrating T-cells. Here we review these multifactorial constraints and mechanisms – elevated immunosuppressive metabolites and enzymes, nutrient insufficiency, hypoxia, increased acidity, immense amounts of extracellular ATP and adenosine, dysregulated bioenergetic and purinergic signalling, and ionic imbalance - that operate in the TME and collectively suppress T-cell function. We discuss how scientific advances could help overcome the complex TME obstacles for tumour-infiltrating T-lymphocytes, aiming to stimulate further research for developing new therapeutic strategies by harnessing the full potential of the immune system in combating cancer.
The voltage-gated Kv1.3 channel and the Ca
2+-activated IKCa1 K
+ channel are expressed in T cells in a distinct pattern that depends on the state of lymphocyte activation and differentiation. The ...channel phenotype changes during the progression from the resting to the activated cell state and from naı̈ve to effector memory cells, affording promise for specific immunomodulatory actions of K
+ channel blockers. In this article, we review the functional roles of these channels in both naı̈ve cells and memory cells, describe the development of selective inhibitors of Kv1.3 and IKCa1 channels, and provide a rationale for the potential therapeutic use of these inhibitors in immunological disorders.
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