ShK toxin is a structurally defined, 35-residue polypeptide which blocks the voltage-gated Kv1.3 potassium channel in T-lymphocytes and has been identified as a possible immunosuppressant. Our interest lies in the rational design and synthesis of type-III mimetics of protein and polypeptide structure and function. ShK toxin is a challenging target for mimetic design as its binding epitope consists of relatively weakly binding residues, some of which are discontinuous. We discuss here our investigations into the design and synthesis of 1st generation, small molecule mimetics of ShK toxin and highlight any principles relevant to the generic design of type-III mimetics of continuous and discontinuous binding epitopes. We complement our approach with attempted pharmacophore-based database mining.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1023/a:1020214720560 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Structural and functional analyses of nematode-derived antimicrobial peptides support the occurrence of direct mechanisms of worm-microbiota interactions.
Comput Struct Biotechnol J
December 2024
Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
The complex relationships between gastrointestinal (GI) nematodes and the host gut microbiota have been implicated in key aspects of helminth disease and infection outcomes. Nevertheless, the direct and indirect mechanisms governing these interactions are, thus far, largely unknown. In this proof-of-concept study, we demonstrate that the excretory-secretory products (ESPs) and extracellular vesicles (EVs) of key GI nematodes contain peptides that, when recombinantly expressed, exert antimicrobial activity in vitro against .
View Article and Find Full Text PDFStructure-function relationships in ShKT domain peptides: ShKT-Ts1 from the sea anemone Telmatactis stephensoni.
Proteins
February 2024
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Diverse structural scaffolds have been described in peptides from sea anemones, with the ShKT domain being a common scaffold first identified in ShK toxin from Stichodactyla helianthus. ShK is a potent blocker of voltage-gated potassium channels (K 1.x), and an analog, ShK-186 (dalazatide), has completed Phase 1 clinical trials in plaque psoriasis.
View Article and Find Full Text PDFGenomic, functional and structural analyses elucidate evolutionary innovation within the sea anemone 8 toxin family.
BMC Biol
May 2023
School of Biology and Environmental Science, Faculty of Science, Queensland University of Technology, Brisbane, QLD, 4000, Australia.
Article Synopsis
- The study investigates the SA8 peptide family in sea anemones, focusing on the genomic structure and evolutionary changes in two species: Actinia tenebrosa and Telmatactis stephensoni.
- Researchers identified multiple SA8 genes and clusters in both sea anemone species, revealing tissue-specific expression patterns and a unique inverted gene associated with venom.
- Findings indicate that SA8 is a distinct gene family in Actiniarians that has evolved through structural changes, ultimately being integrated into the venom system of T. stephensoni, although its functional activity remains unclear.
Immunocytoprotection after reperfusion with Kv1.3 inhibitors has an extended treatment window for ischemic stroke.
Front Pharmacol
April 2023
Department of Pharmacology, School of Medicine, University of California, Davis, Davis, CA, United States.
Mechanical thrombectomy has improved treatment options and outcomes for acute ischemic stroke with large artery occlusion. However, as the time window of endovascular thrombectomy is extended there is an increasing need to develop immunocytoprotective therapies that can reduce inflammation in the penumbra and prevent reperfusion injury. We previously demonstrated, that by reducing neuroinflammation, K1.
View Article and Find Full Text PDFKv1.3 Channel Up-Regulation in Peripheral Blood T Lymphocytes of Patients With Multiple Sclerosis.
Front Pharmacol
September 2021
National and Kapodistrian University of Athens, Medical School, Athens, Greece.
Voltage-gated Kv1.3 potassium channels are key regulators of T lymphocyte activation, proliferation and cytokine production, by providing the necessary membrane hyper-polarization for calcium influx following immune stimulation. It is noteworthy that an accumulating body of and evidence links these channels to multiple sclerosis pathophysiology.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!