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Site specific protein modifications

A protein and target protein technology, applied in the field of amino functional groups, can solve problems such as the difficulty of selective derivatization of proteins/peptides

Active Publication Date: 2017-04-19
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Selective derivatization of proteins / peptides is a very difficult task despite recombinant approaches

Method used

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  • Site specific protein modifications
  • Site specific protein modifications
  • Site specific protein modifications

Examples

Experimental program
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Embodiment approach

[0091] Various embodiments of the invention are described herein. It will be appreciated that features specified in each embodiment may be combined with other specified features to provide other embodiments.

[0092] In embodiment 1, the present invention relates to a method for modifying a target protein or target peptide at an amino functional group of an N-terminal amino acid, said method comprising the steps of:

[0093] c. modifying the target protein or target peptide such that the resulting protein or peptide contains a histidine amino acid at a position adjacent to the N-terminal amino acid;

[0094] d. Contacting a protein or peptide containing a histidine amino acid at a position adjacent to the N-terminal amino acid with an acylation compound at a pH below 6 to form a modified protein or peptide.

[0095] In embodiment 2, the invention relates to a method according to embodiment 1, wherein said protein or peptide containing a histidine amino acid at a position adja...

Embodiment approach 16

[0124] Embodiment 16, the invention relates to the method according to embodiment 14, wherein R 1 is the fatty acid (FA) moiety. Examples of fatty acids are fatty acids with at least one carboxylic acid (e.g. 1, 2, 3 or 4 CO 2 H) C substituted and optionally further substituted with hydroxyl 6-70 Alkyl, C 6-70 Alkenyl, C 6-70 Alkynyl chain. The fatty acid (FA) is preferably via the linker L 1 Conjugate to target protein or target peptide. In embodiment 16A, the invention relates to a method according to embodiment 16, wherein R 1 Acids selected from:

[0125]

[0126] R 2 is CO 2 H, H;

[0127] R 3 , R 4 and R 5 independently of each other are H, OH, CO 2 H, -CH=CH 2 or –C ＝ CH;

[0128] Ak 1 is branched C 6 -C 30 alkylene;

[0129] q, r and p are independently of each other an integer between 6 and 30; and wherein the junction is CO 2 H functional group; or any one of amides, esters, or pharmaceutically acceptable salts thereof.

[0130] In embodimen...

Embodiment 1

[0364] Example 1: Step b of the present invention using AHNGDLKF-NH2 and sulfo-NHS-LC biotin as acylating agents.

[0365] LCMS product retention time: 1.81 min; measured value: [M+H] + =1239.63; calculated value: [M+H] + =1239.6200).

[0366] Plotted data (using MALDI LIFT method): Biotin + Alanine: Measured value: [M+H] + = about 411; Calculated: [M+H]+ = 411.21). Biotin+AH: measured value: [M+H] + =548.27; Calculated value: [M+H] + = 548.27). No individual alanine mass was detected.

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Abstract

The present invention relates to method and reagents for use in site-selective modification of protein and peptide. The site selective modification is a selective derivation of the amino functionality at the N-terminus of the protein or the polypeptide using the presence of a neighboring histidine amino acid to increase the reactivity of the N-terminal amino functionality. The modified proteins or peptides obtained by method of the invention may be used for imaging study or therapeutic uses.

Description

[0001] field of invention [0002] The present invention generally relates to novel methods for introducing modifying groups into proteins or polypeptides. In particular, the present invention relates to the selective derivatization of amino functions at the N-terminus of proteins or polypeptides by taking advantage of the presence of adjacent histidine amino acids to increase the reactivity of the N-terminal amino function. [0003] Background of the invention [0004] It is well known that properties and characteristics of proteins or peptides can be modified by conjugating groups to the protein or peptide. In general, this type of conjugation usually requires some functional group in the protein to react with another functional group in the conjugating group. Amino groups, such as the N-terminal amino group or the ε-amino group in lysine residues, have been used for this purpose in combination with suitable acylating agents. Often it is desirable or necessary to control th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K1/107C07K1/13C07K19/00A61K47/60
CPCC07K1/1077C07K1/13C07K14/475C07K14/705C07K2319/21C07K2319/50C07K2319/30A61K47/60A61K47/542A61K47/64A61K47/68A61K51/088A61P43/00C07K1/1075C07K16/00
Inventor A·R·尤塞拉袁骏C·娄
Owner NOVARTIS AG