CHAPTER 10. Case Study 2: Transforming a Toxin into a Therapeutic: the Sea Anemone Potassium Channel Blocker ShK Toxin for Treatment of Autoimmune Diseases

Norton, Raymond S.; Pennington, Michael W.; Beeton, Christine

doi:10.1039/9781849737876-00255

Cited by 12 publications

(12 citation statements)

References 33 publications

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“…Consequently, ShK-186 prevents and treats disease expression in rat models of delayed type hypersensitivity, multiple sclerosis, and rheumatoid arthritis mediated by Th1/Th17 lymphocytes without preventing the clearance of acute bacterial and viral infections and without inducing toxicity in rodents or non-human primates (11,12,18,19). ShK-186 has successfully completed Phase 1a first-in-man safety clinical trials (20).…”

Section: Cells (8) Targeting T Em Lymphocytes Without Affecting Ccr7mentioning

confidence: 99%

“…However, all of these diseases are mediated by Th1/Th17 lymphocytes, whereas Th2 lymphocytes play a role in disease pathogenesis in a large number of patients with asthma. The targeting of K V 1.3 channels in T lymphocytes for the treatment of asthma has been hypothesized in recent reviews by us and our collaborators based on the successful inhibition of Th1/ Th17 lymphocytes in autoimmune diseases as ShK-186, and other K V 1.3 channel blockers have been shown to inhibit the secretion of IL-2, IFN␥, and IL-17A by T EM lymphocytes (14,15,20,37). However, this study is to our knowledge the first to test the efficacy of a K V 1.3 channel blocker in inhibiting the function of human Th2 lymphocytes isolated from subjects with asthma and in treating an animal model of asthma.…”

Section: Cd45ramentioning

confidence: 99%

“…In contrast, current approved medications that target T lymphocytes to treat these diseases are not selective for CD45RA Ϫ CCR7 Ϫ T EM lymphocytes and are known to induce significant immune side effects, such as an increase in the risk of infections or tumors in addition to non-immune side effects through affecting other organ systems. ShK-186 has already successfully undergone Phase 1a first-in-man safety clinical trials and is currently undergoing Phase 1b clinical trials (20).…”

Section: Cd45ramentioning

confidence: 99%

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Blocking KV1.3 Channels Inhibits Th2 Lymphocyte Function and Treats a Rat Model of Asthma

Koshy

Huq²,

Tanner³

et al. 2014

Journal of Biological Chemistry

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Section: Cells (8) Targeting T Em Lymphocytes Without Affecting Ccr7mentioning

confidence: 99%

Section: Cd45ramentioning

confidence: 99%

Section: Cd45ramentioning

confidence: 99%

See 1 more Smart Citation

Blocking KV1.3 Channels Inhibits Th2 Lymphocyte Function and Treats a Rat Model of Asthma

Koshy

Huq²,

Tanner³

et al. 2014

Journal of Biological Chemistry

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“…These peptides had improved stability profiles relative to ShK-186 and ShK-170 and demonstrated similar selectivity profiles to ShK-186. ShK-186 was well tolerated in Phase 1a and 1b clinical trials in healthy volunteers and has been advanced by Kineta Inc. (Seattle, WA, USA) into Phase 1b-2a clinical trials with patients [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

Development of Highly Selective Kv1.3-Blocking Peptides Based on the Sea Anemone Peptide ShK

et al. 2015

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ShK, from the sea anemone Stichodactyla helianthus, is a 35-residue disulfide-rich peptide that blocks the voltage-gated potassium channel Kv1.3 at ca. 10 pM and the related channel Kv1.1 at ca. 16 pM. We developed an analog of this peptide, ShK-186, which is currently in Phase 1b-2a clinical trials for the treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. While ShK-186 displays a >100-fold improvement in selectivity for Kv1.3 over Kv1.1 compared with ShK, there is considerable interest in developing peptides with an even greater selectivity ratio. In this report, we describe several variants of ShK that incorporate p-phophono-phenylalanine at the N-terminus coupled with internal substitutions at Gln16 and Met21. In addition, we also explored the combinatorial effects of these internal substitutions with an alanine extension at the C-terminus. Their selectivity was determined by patch-clamp electrophysiology on Kv1.3 and Kv1.1 channels stably expressed in mouse fibroblasts. The peptides with an alanine extension blocked Kv1.3 at low pM concentrations and exhibited up to 2250-fold selectivity for Kv1.3 over Kv1.1. Analogs that incorporates p-phosphono-phenylalanine at the N-terminus blocked Kv1.3 with IC50s in the low pM range and did not affect Kv1.1 at concentrations up to 100 nM, displaying a selectivity enhancement of >10,000-fold for Kv1.3 over Kv1.1. Other potentially important Kv channels such as Kv1.4 and Kv1.6 were only partially blocked at 100 nM concentrations of each of the ShK analogs.

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“…We then discuss how these methods have been employed to generate analogs of peptide toxins with improved selectivity profiles, using ShK and HsTX1 toxins as examples. There is increasing acceptance of peptides as human pharmaceuticals, as illustrated by the abundance of peptides amongst recent US FDA-approved biologics [17], even though they present a number of challenges in terms of delivery, stability and circulating half-life [18]. We therefore expect the methods reviewed here to find widespread application in the development of new peptide therapeutics.…”

mentioning

confidence: 99%

Computational Approaches for Designing Potent and Selective Analogs of Peptide Toxins as Novel Therapeutics

Kuyucak

Norton

2014

Future Med. Chem.

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Peptide toxins provide valuable therapeutic leads for many diseases. As they bind to their targets with high affinity, potency is usually ensured. However, toxins also bind to off-target receptors, causing potential side effects. Thus, a major challenge in generating drugs from peptide toxins is ensuring their specificity for their intended targets. Computational methods can play an important role in solving such design problems through construction of accurate models of receptor–toxin complexes and calculation of binding free energies. Here we review the computational methods used for this purpose and their application to toxins targeting ion channels. We describe ShK and HsTX1 toxins, high-affinity blockers of the voltage-gated potassium channel Kv1.3, which could be developed as therapeutic agents for autoimmune diseases.

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CHAPTER 10. Case Study 2: Transforming a Toxin into a Therapeutic: the Sea Anemone Potassium Channel Blocker ShK Toxin for Treatment of Autoimmune Diseases

Cited by 12 publications

References 33 publications

Blocking KV1.3 Channels Inhibits Th2 Lymphocyte Function and Treats a Rat Model of Asthma

Blocking KV1.3 Channels Inhibits Th2 Lymphocyte Function and Treats a Rat Model of Asthma

Development of Highly Selective Kv1.3-Blocking Peptides Based on the Sea Anemone Peptide ShK

Computational Approaches for Designing Potent and Selective Analogs of Peptide Toxins as Novel Therapeutics

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