- |||||||||| dalazatide (ShK-186) / Kineta, KPI Therap
Journal: KCNE4-dependent modulation of Kv1.3 pharmacology. (Pubmed Central) - Jul 26, 2024
Various leukocyte types expressing different Kv1.3/KCNE4 configurations participate in the immune response. Our data provide evidence that the presence of these variable architectures, which affect both the structure of the complex and their pharmacology, should be considered when developing putative therapeutic approaches.
- |||||||||| telmisartan / Generic mfg.
Journal: Structure-function relationships in ShKT domain peptides: ShKT-Ts1 from the sea anemone Telmatactis stephensoni. (Pubmed Central) - Jan 9, 2024
We show that either a buried dyad that does not become exposed during MD simulations, or a partially exposed dyad that becomes buried during MD simulations, correlates with weak or absent activity against K 1.x channels. Therefore, structure determination coupled with MD simulations, may be used to predict whether new sequences belonging to the ShKT family may act as potassium channel blockers.
- |||||||||| dalazatide (ShK-186) / Kineta, KPI Therap
Review, Journal, IO biomarker: Structure of the voltage-gated potassium channel K1.3: Insights into the inactivated conformation and binding to therapeutic leads. (Pubmed Central) - Sep 15, 2023
Binding of the peptide dalazatide (ShK-186) and an antibody-ShK fusion to the external vestibule of K1.3 narrows and stabilizes the selectivity filter in the open-conducting conformation, although K efflux is blocked by the peptide occluding the pore through the interaction of ShK-Lys22 with the backbone carbonyl of K1.3-Tyr447 in the selectivity filter...Binding of the anti-K1.3 nanobody A0194009G09 to the turret and residues in the external loops of the voltage-sensing domain enhances the dilation of the outer selectivity filter in an exaggerated inactivated conformation. These studies lay the foundation to further define the mechanism of slow inactivation in K channels and can help guide the development of future K1.3-targeted immuno-therapeutics.
- |||||||||| dalazatide (ShK-186) / Kineta, KPI Therap
Journal: Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug. (Pubmed Central) - Feb 26, 2022
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.
- |||||||||| dalazatide (ShK-186) / Kineta, KPI Therap
Review, Journal: The Kv1.3 K channel in the immune system and its "precision pharmacology" using peptide toxins. (Pubmed Central) - Dec 16, 2021
To date, the highest affinity Kv1.3 inhibitors with the best Kv1.3 selectivity are the engineered analogues of the sea anemone peptide ShK (e.g., ShK-186), the engineered scorpion toxin HsTx1[R14A] and the natural scorpion toxin Vm24...Despite the significant progress in the field of Kv1.3 molecular pharmacology several progressive questions remain to be elucidated and discussed here. These include the conjugation of the peptides to carriers to increase the residency time of the peptides in the circulation (e.g., PEGylation and engineering the peptides into antibodies), use of rational drug design to create novel peptide inhibitors and understanding the potential off-target effects of Kv1.3 inhibition.
- |||||||||| dalazatide (ShK-186) / Kineta, KPI Therap
Review, Journal: Discovery of K 1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges. (Pubmed Central) - Oct 30, 2021
Selectivity of dalatazide (ShK-186), a synthetic derivate of the sea anemone toxin ShK, was achieved by chemical modification and has successfully reached clinical trials as a potential therapeutic for treating autoimmune diseases...Some small-molecule inhibitors with well-defined structure-activity relationships have been optimized for selective delivery to mitochondria, and these offer therapeutic potential for the treatment of cancers. This overview of K 1.3 inhibitors and methodologies is designed to provide a good starting point for drug discovery to identify novel effective K 1.3 modulators against this target in the future.
- |||||||||| dalazatide (ShK-186) / Kineta, KPI Therap
Review, Journal: The voltage-gated potassium channel K1.3 as a therapeutic target for venom-derived peptides. (Pubmed Central) - Jan 5, 2021
Moreover, an analogue of the sea anemone peptide ShK (known as dalazatide) has successfully completed Phase 1 clinical trials in mild-to-moderate plaque psoriasis...Venom-derived peptides that have been reported recently to target K1.3 are also described. The increasing number of autoimmune and other conditions in which K1.3 is upregulated and is therefore a potential therapeutic target, combined with the fact that many venom-derived peptides are potent inhibitors of K1.3, suggests that venoms are likely to continue to serve as a rich source of new pharmacological tools and therapeutic leads targeting this channel.
- |||||||||| dalazatide (ShK-186) / Kineta, KPI Therap
Review, Journal: Kv1.3 Channel as a Key Therapeutic Target for Neuroinflammatory Diseases: State of the Art and Beyond. (Pubmed Central) - Jan 30, 2020
One of the synthetic analogs ShK-186, being developed as a therapeutic for autoimmune diseases, has successfully completed first-in-man Phase 1 trials. In addition to addressing the recent progress on the studies underlying the pharmacological characterizations of ShK on MS, the review will also explore the possibility for clinical treatment of ShK-like Kv1.3 blocking polypeptides on other neuroinflammatory diseases.
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