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Protoxin-II variants and methods of use

  • US 9,624,280 B2
  • Filed: 10/03/2014
  • Issued: 04/18/2017
  • Est. Priority Date: 10/03/2013
  • Status: Active Grant
First Claim
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1. An isolated Protoxin-II variant comprising the sequence X1X2X3CX4X5WX6QX7CX8X9X10X11X12CCX13X14FX15CX16LWCX17KKLW (SEQ ID NO:

  • 403), whereinX1 is G, P, A or deleted;

    X2 is P, A or deleted;

    X3 is S, Q, A, R or Y;

    X4 is Q, R, K, A or S;

    X5 is K, S, Q or R;

    X6 is M or F;

    X7 is T, S, R, K or Q;

    X8 is D or T;

    X9 is S, A or R;

    X10 is E, R, N, K, T or Q;

    X11 is R or K;

    X12 is K, Q, S or A;

    X13 is E, Q or D;

    X14 is G or Q;

    X15 is V or S;

    X16 is R or T; and

    X17 is K or R;

    optionally having an N-terminal extension or a C-terminal extension,wherein the polypeptide inhibits human Nav1.7 activity with an IC50 value of about 1×

    10

    7
    M or less,wherein the IC50 value is measured using a membrane depolarization assay using fluorescence resonance energy transfer (FRET) in the presence of 25×

    10

    6
    M 3-veratroylveracevine in HEK293 cells stably expressing human Nav1.7 and using bis-(1,3-diethylthiobarbituric acid)trimethine oxonol as an electron acceptor and Trisodium 8-octadecyloxypyrene-1,3,6-trisulfonate as a donor by exciting the donor at 390-420 nm and measuring FRET at 515-575 nm.

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