Potent Kv1.3 inhibitors from correolide—modification of the C18 position

Bao, Jianming; Miao, Shouwu; Kayser, Frank; Котляр, А; Baker, Robert K.; Doss, George A.; Felix, John P.; Bugianesi, Randal M.; Slaughter, Robert S.; Kaczorowski, Gregory J.; García, María L.; Ha, Sookhee; Castonguay, Laurie A.; Koo, Gloria C.; Shah, Kashmira; Springer, Marty S.; Staruch, Mary Jo; Parsons, William H.; Rupprecht, Kathleen M.

doi:10.1016/j.bmcl.2004.10.058

Cited by 19 publications

(6 citation statements)

References 12 publications

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“…The first small-molecule Kv1.3 blockers with nanomolar affinity that were discovered-iminodihydroquinolines WIN-17317 and CP-339818 and the benzhydryl piperidine UK-78282-also block sodium channels (Wanner et al, 1999) and the neuronal Kv1.4 channel (Hanson et al, 1999). The small-molecule Kv1.3 inhibitors developed by Merck-correolide (Felix et al, 1999;Hanner et al, 1999;Koo et al, 1999;Bao et al, 2005), cyclohexyl-subsituted benzamides (Schmalhofer et al, 2002) and candelalides A-C (Singh et al, 2001)-are poorly selective for Kv1.3. Psora-4, the most potent smallmolecule Kv1.3 blocker (K d , 3 nM) is only 16-to 20-fold selective for Kv1.3 over Kv1.1 and Kv1.2 and 2.5-fold selective over the cardiac Kv1.5 channel (Vennekamp et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Targeting Effector Memory T Cells with a Selective Peptide Inhibitor of Kv1.3 Channels for Therapy of Autoimmune Diseases

et al. 2005

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The voltage-gated Kv1.3 K ϩ channel is a novel target for immunomodulation of autoreactive effector memory T (T EM ) cells that play a major role in the pathogenesis of autoimmune diseases. We describe the characterization of the novel peptide ShK(L5) that contains L-phosphotyrosine linked via a nine-atom hydrophilic linker to the N terminus of the ShK peptide from the sea anemone Stichodactyla helianthus. ShK(L5) is a highly specific Kv1.3 blocker that exhibits 100-fold selectivity for Kv1.3 (K d ϭ 69 pM) over Kv1.1 and greater than 250-fold selectivity over all other channels tested. ShK(L5) suppresses the proliferation of human and rat T EM cells and inhibits interleukin-2 production at picomolar concentrations. Naive and central memory human T cells are initially 60-fold less sensitive than T EM cells to ShK(L5) and then become resistant to the peptide during activation by up-regulating the calcium-activated K Ca 3.1 channel. ShK(L5) does not exhibit in vitro cytotoxicity on mammalian cell lines and is negative in the Ames test. It is stable in plasma and when administered once daily by subcutaneous injection (10 g/kg) attains "steady state" blood levels of ϳ300 pM. This regimen does not cause cardiac toxicity assessed by continuous EKG monitoring and does not alter clinical chemistry and hematological parameters after 2-week therapy. ShK(L5) prevents and treats experimental autoimmune encephalomyelitis and suppresses delayed type hypersensitivity in rats. ShK(L5) might prove useful for therapy of autoimmune disorders.

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Section: Discussionmentioning

confidence: 99%

Targeting Effector Memory T Cells with a Selective Peptide Inhibitor of Kv1.3 Channels for Therapy of Autoimmune Diseases

et al. 2005

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“…Unfortunately, correolide was not specific for Kv1.3 as it bound with equal potency to all Kv1-family channels [63]. Other simplified analogues were synthesized including the C18-correolide analogue 43 ( 7 ) (Figure 1) which inhibited Kv1.3 with an IC 50 of 37 nM in 86 Rb-flux assays [64]. To date, the Kv1.3 specificity of this compound has not been reported as the synthesis of these analogues is hampered by the limited supply of the natural parent compound [64].…”

Section: Small Molecule Kv13 Blockersmentioning

confidence: 99%

Use of Kv1.3 Blockers for Inflammatory Skin Conditions

Nguyen

Howard

Neale

et al. 2010

CMC

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Recent results using animal models of inflammatory skin conditions have shown that blockers of the voltage-gated potassium channel, Kv1.3 hold great promise for clinical utility. Kv1.3 blockers act as immunosuppressants by modulating the various subsets of inflammatory T and B cells involved in autoimmune disorders. While peptidic inhibitors based on naturally occurring venoms demonstrate potent and selective Kv1.3 blockade, these require parenteral administration and may face potential immunogenicity problems. Small molecule blockers show considerable diversity, however selectivity over other Kv1- family channels has been difficult to achieve. More recent advances have added to the evidence that Kv1.3 channels are a suitable therapeutic target and that the development of novel and selective agents will herald new drugs for inflammatory skin disorders.

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“…In this mode, neither epoxy group nor seven-membered ring interacts with K+. Such a binding mode may explain why elimination of the epoxy group and removal of the carbonyl oxygen from the seven-membered ring does not abolish the channel-blocking activity of correolide [28]. The same correolide-sensing residues that contribute to correolide binding in model 2/4 also contribute to the ligand binding in model 1/3/5 (Table 2).…”

Section: Resultsmentioning

confidence: 99%

Untitled

Bruhova

Zhorov

2007

BMC Struct Biol

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BackgroundCorreolide, a nortriterpene isolated from the Costa Rican tree Spachea correa, is a novel immunosuppressant, which blocks Kv1.3 channels in human T lymphocytes. Earlier mutational studies suggest that correolide binds in the channel pore. Correolide has several nucleophilic groups, but the pore-lining helices in Kv1.3 are predominantly hydrophobic raising questions about the nature of correolide-channel interactions.ResultsWe employed the method of Monte Carlo (MC) with energy minimization to search for optimal complexes of correolide in Kv1.2-based models of the open Kv1.3 with potassium binding sites 2/4 or 1/3/5 loaded with K+ ions. The energy was MC-minimized from many randomly generated starting positions and orientations of the ligand. In all the predicted low-energy complexes, oxygen atoms of correolide chelate a K+ ion. Correolide-sensing residues known from mutational analysis along with the ligand-bound K+ ion provide major contributions to the ligand-binding energy. Deficiency of K+ ions in the selectivity filter of C-type inactivated Kv1.3 would stabilize K+-bound correolide in the inner pore.ConclusionOur study explains the paradox that cationic and nucleophilic ligands bind to the same region in the inner pore of K+ channels and suggests that a K+ ion is an important determinant of the correolide receptor and possibly receptors of other nucleophilic blockers of the inner pore of K+ channels.

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Potent Kv1.3 inhibitors from correolide—modification of the C18 position

Cited by 19 publications

References 12 publications

Targeting Effector Memory T Cells with a Selective Peptide Inhibitor of Kv1.3 Channels for Therapy of Autoimmune Diseases

Targeting Effector Memory T Cells with a Selective Peptide Inhibitor of Kv1.3 Channels for Therapy of Autoimmune Diseases

Use of Kv1.3 Blockers for Inflammatory Skin Conditions

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