POLYPEPTIDES COMPRISING A MODIFIED BACTERIOPHAGE G3P AMINO ACID SEQUENCE WITH REDUCED IMMUNOGENICITY

摘要

The invention relates to polypeptides that comprise a portion of filamentous bacteriophage gene 3 protein (g3p) sufficient to bind to and/or disaggregate amyloid, e.g., the N1-N2 portion of g3p and mutants and fragments thereof wherein that g3p amino acid sequence has been modified through amino acid substitution to be substantially less immunogenic than the corresponding wild-type g3p amino acid sequence when used in vivo. The polypeptides of the invention retain their ability bind to and/or disaggregate amyloid. The invention relates furthermore to the use of these variant g3p-polypeptides in the treatment and/or prevention of diseases associated with misfolding or aggregation of amyloid.

主权项

1. A polypeptide comprising a variant of a starting amino acid sequence, wherein the starting amino acid sequence is selected from: amino acids 1-217 of SEQ ID NO:1, amino acids 1-217 of SEQ ID NO:3, amino acids 1-217 of SEQ ID NO:7, and mutants of any of the foregoing having one or more of the following modifications: substitution of VVV at amino acids 43-45 with AAA; substitution C53W; deletion of amino acids 96-103; substitution of QPP at amino acids 212-214 with AGA; substitutions W181A, F190A and F194A; deletion of amino acid 1; and deletion of amino acids 1 and 2, wherein:
(a) the polypeptide binds to and/or disaggregates amyloid; (b) the polypeptide has reduced immunogenicity as compared to a corresponding polypeptide comprising the starting amino acid sequence; (c) the variant has from 1 to 9 amino acid substitutions as compared to the starting amino acid sequence, wherein each amino acid substitution is selected from the group of amino acid substitutions set forth below:Amino Acid presentAminoin the Starting AminoAcid #Acid SequenceAmino Acid Substitutions48GH, K, R, S, T, D, P50EG, H, K, P, R51TG, H, K, R, P, Q, N, W53CF, H, K, N, Q, R, W, Y54YG, H, K, R, P56TG, H, K, R, P135MA, D, G, K, N, T, H, R, C, E, P, Q, S137QD, E138ND, E, G, H, P, Q, S, T140RD, E, H, Q, A, G, M, N, P, S, Y141FD, E143NA, G173SG, P, K, D, H, R, T174KR175AG, H, K, P, R176MG, H, K, N, R, P, Q, W178DG, N, Q, S, T, F, H, K, R, W, Y179AH, K, P, R181WG, H, K, R, P and (d) when the starting amino acid sequence is amino acids 1-217 of SEQ ID NO:1 any of the 1 to 9 amino acid substitutions is optionally additionally selected from the group of amino acid substitutions set forth below:Amino AcidAminopresent in the StartingAcid #Amino Acid SequenceAmino Acid Substitutions215VS, T, C, D, E, F, H, K, N, P, Q, R218GC, E, N, P, Q, S, T, A, H, W220GE, D, F, W, M, Y221SD, E, G223GD, P, E, K, N, R, T