Engineering potent and selective analogues of GpTx-1, a

J. Med. Chem. · Mar 2015

Engineering potent and selective analogues of GpTx-1, a tarantula venom peptide antagonist of the Na(V)1.7 sodium channel.

NaV1.7 is a voltage-gated sodium ion channel implicated by human genetic evidence as a therapeutic target for the treatment of pain. Screening fractionated venom from the tarantula Grammostola porteri led to the identification of a 34-residue peptide, termed GpTx-1, with potent activity on NaV1.7 (IC50 = 10 nM) and promising selectivity against key NaV subtypes (20× and 1000× over NaV1.4 and NaV1.5, respectively). ⋯ Substitution of Ala for Phe at position 5 conferred 300-fold selectivity against NaV1.4. A structure-guided campaign afforded additive improvements in potency and NaV subtype selectivity, culminating in the design of [Ala5,Phe6,Leu26,Arg28]GpTx-1 with a NaV1.7 IC50 value of 1.6 nM and >1000× selectivity against NaV1.4 and NaV1.5.

explore more… or not…
- Justin K Murray, Joseph Ligutti, Dong Liu, Anruo Zou, Leszek Poppe, Hongyan Li, Kristin L Andrews, Bryan D Moyer, Stefan I McDonough, Philippe Favreau, Reto Stöcklin, and Les P Miranda.
- Departments of Therapeutic Discovery, ‡Neuroscience, and §Pharmacokinetics & Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
- J. Med. Chem. 2015 Mar 12; 58 (5): 2299-314.
AbstractNaV1.7 is a voltage-gated sodium ion channel implicated by human genetic evidence as a therapeutic target for the treatment of pain. Screening fractionated venom from the tarantula Grammostola porteri led to the identification of a 34-residue peptide, termed GpTx-1, with potent activity on NaV1.7 (IC50 = 10 nM) and promising selectivity against key NaV subtypes (20× and 1000× over NaV1.4 and NaV1.5, respectively). NMR structural analysis of the chemically synthesized three disulfide peptide was consistent with an inhibitory cystine knot motif. Alanine scanning of GpTx-1 revealed that residues Trp(29), Lys(31), and Phe(34) near the C-terminus are critical for potent NaV1.7 antagonist activity. Substitution of Ala for Phe at position 5 conferred 300-fold selectivity against NaV1.4. A structure-guided campaign afforded additive improvements in potency and NaV subtype selectivity, culminating in the design of [Ala5,Phe6,Leu26,Arg28]GpTx-1 with a NaV1.7 IC50 value of 1.6 nM and >1000× selectivity against NaV1.4 and NaV1.5.

Pubmed Full text Copy Citation Plaintext

Add institutional full text...
Notes
Knowledge, pearl, summary or comment to share?

300 characters remaining

help

You can also include formatting, links, images and footnotes in your notes

Simple formatting can be added to notes, such as *italics*, _underline_ or **bold**.

Superscript can be denoted by <sup>text</sup> and subscript <sub>text</sub>.

Numbered or bulleted lists can be created using either numbered lines 1. 2. 3., hyphens - or asterisks *.

Links can be included with: [my link to pubmed](http://pubmed.com)

Images can be included with: ![alt text](https://bestmedicaljournal.com/study_graph.jpg "Image Title Text")

For footnotes use [^1](This is a footnote.) inline.

Or use an inline reference [^1] to refer to a longer footnote elseweher in the document [^1]: This is a long footnote..
hide…

Engineering potent and selective analogues of GpTx-1, a tarantula venom peptide antagonist of the Na(V)1.7 sodium channel.

Notes

300 characters remaining

help

You can also include formatting, links, images and footnotes in your notes

What will the 'Medical Journal of You' look like?

Start your free 21 day trial now.