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

Kuyucak, Serdar; Norton, Raymond S.

doi:10.4155/fmc.14.98

Cited by 26 publications

(25 citation statements)

References 97 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Some marine toxins found in sea anemones target Kv1 channels in which block leads to neuronal hyperexcitability and muscle spasms. These marine toxins have been shown to have important therapeutic applications in the treatment of autoimmune diseases including multiple sclerosis, rheumatoid arthritis, and diabetes [101,102].…”

Section: Cnidarian Peptides That Inhibit Kv1 Channelsmentioning

confidence: 99%

Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds

et al. 2020

View full text Add to dashboard Cite

Toxins from marine animals provide molecular tools for the study of many ion channels, including mammalian voltage-gated potassium channels of the Kv1 family. Selectivity profiling and molecular investigation of these toxins have contributed to the development of novel drug leads with therapeutic potential for the treatment of ion channel-related diseases or channelopathies. Here, we review specific peptide and small-molecule marine toxins modulating Kv1 channels and thus cover recent findings of bioactives found in the venoms of marine Gastropod (cone snails), Cnidarian (sea anemones), and small compounds from cyanobacteria. Furthermore, we discuss pivotal advancements at exploiting the interaction of κM-conotoxin RIIIJ and heteromeric Kv1.1/1.2 channels as prevalent neuronal Kv complex. RIIIJ’s exquisite Kv1 subtype selectivity underpins a novel and facile functional classification of large-diameter dorsal root ganglion neurons. The vast potential of marine toxins warrants further collaborative efforts and high-throughput approaches aimed at the discovery and profiling of Kv1-targeted bioactives, which will greatly accelerate the development of a thorough molecular toolbox and much-needed therapeutics.

show abstract

Section: Cnidarian Peptides That Inhibit Kv1 Channelsmentioning

confidence: 99%

Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Testing of 144 (20kDa-PEG-ShK) revealed that it retained sub-nanomolar potency in inhibiting Kv1. 3 and T-cell cytokine responses (Table 5) and exhibited a prolonged half-life in rats (mean residence time of 37 h, Supporting Information Table S2). In agreement 20 with other N-terminally derivatized ShK analogs, 35 such as 143 (phosphotyrosine-AEEA-ShK), which have been reported to have increased selectivity for Kv1.3, we also found 144 to be 5-fold more potent against Kv1.3 than against Kv1.1.…”

Section: Impact Of Conjugation On Potency Selectivity and Pharmacokmentioning

confidence: 98%

“…14 Other potential disease indications mediated by Kv1. 3 have also been elucidated. 15 For toxin peptides to be safe and well-tolerated, undesirable off-target activities and poor pharmacokinetic profiles, particularly rapidly rising and diminishing circulating levels, must be addressed.…”

Section: Introductionmentioning

confidence: 99%

Pharmaceutical Optimization of Peptide Toxins for Ion Channel Targets: Potent, Selective, and Long-Lived Antagonists of Kv1.3

Murray¹,

Qian²,

Liu³

et al. 2015

J. Med. Chem.

View full text Add to dashboard Cite

To realize the medicinal potential of peptide toxins, naturally occurring disulfide-rich peptides, as ion channel antagonists, more efficient pharmaceutical optimization technologies must be developed. Here, we show that the therapeutic properties of multiple cysteine toxin peptides can be rapidly and substantially improved by combining direct chemical strategies with high-throughput electrophysiology. We applied whole-molecule, brute-force, structure-activity analoging to ShK, a peptide toxin from the sea anemone Stichodactyla helianthus that inhibits the voltage-gated potassium ion channel Kv1.3, to effectively discover critical structural changes for 15× selectivity against the closely related neuronal ion channel Kv1.1. Subsequent site-specific polymer conjugation resulted in an exquisitely selective Kv1.3 antagonist (>1000× over Kv1.1) with picomolar functional activity in whole blood and a pharmacokinetic profile suitable for weekly administration in primates. The pharmacological potential of the optimized toxin peptide was demonstrated by potent and sustained inhibition of cytokine secretion from T cells, a therapeutic target for autoimmune diseases, in cynomolgus monkeys.

show abstract

“…SCTX peptides are also a focus for agrochemical lead compounds for novel invertebrate-specific insecticides (Ortiz and Possani, 2015). Continuing SCTX peptide research has great potential for the development of novel pharmaceuticals capable of specifically modulating channel function (Kuyucak and Norton, 2014). Such development has obvious implications towards the treatment of a range of chronic medical conditions including neurodegenerative and cardiovascular disease (Fuller et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Scorpion toxin peptide action at the ion channel subunit level

Housley

Liddell

et al. 2017

Neuropharmacology

View full text Add to dashboard Cite

a b s t r a c tThis review categorizes functionally validated actions of defined scorpion toxin (SCTX) neuropeptides across ion channel subclasses, highlighting key trends in this rapidly evolving field. Scorpion envenomation is a common event in many tropical and subtropical countries, with neuropharmacological actions, particularly autonomic nervous system modulation, causing significant mortality. The primary active agents within scorpion venoms are a diverse group of small neuropeptides that elicit specific potent actions across a wide range of ion channel classes. The identification and functional characterisation of these SCTX peptides has tremendous potential for development of novel pharmaceuticals that advance knowledge of ion channels and establish lead compounds for treatment of excitable tissue disorders. This review delineates the unique specificities of 320 individual SCTX peptides that collectively act on 41 ion channel subclasses. Thus the SCTX research field has significant translational implications for pathophysiology spanning neurotransmission, neurohumoral signalling, sensori-motor systems and excitation-contraction coupling.This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.'

show abstract

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

Cited by 26 publications

References 97 publications

Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds

Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds

Pharmaceutical Optimization of Peptide Toxins for Ion Channel Targets: Potent, Selective, and Long-Lived Antagonists of Kv1.3

Scorpion toxin peptide action at the ion channel subunit level

Contact Info

Product

Resources

About