# US 8,569,463 B2 · Method of covalently modifying proteins with organic molecules to prevent aggregation > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,569,463 B2 - Document ID: US8569463B2 - Status: Granted - Kind: B2 - Application number: 12/766,063 - Filed: 2010-04-23 - Published: 2010-10-28 - Granted: 2013-10-29 - Earliest claimed: 2009-04-23 - Assignees: Syracuse University - Applicants: Yan-Yeung Luk; DaWei Cui; Debjyoti Bandyopadhyay; Deepali Prashar; Preeti Sejwal; Karen Simon - Inventors: Yan-Yeung Luk; DaWei Cui; Debjyoti Bandyopadhyay; Deepali Prashar; Preeti Sejwal; Karen Simon - Web page: https://patentgrep.com/patent/US8569463B2 ## CPC - C07K 1/1077: {by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids} - A61K 39/39591: {Stabilisation, fragmentation} - A61K 41/0004: {Homeopathy; Vitalisation; Resonance; Dynamisation, e.g. esoteric applications; Oxygenation of blood} - C07K 1/006: {of peptides containing derivatised side chain amino acids} - C07K 1/13: Labelling of peptides - A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## Abstract A system and method for preventing protein aggregation is developed by covalent modification of proteins with organic molecules that can preserve the native protein folding. Proteins are covalently modified with sugar alcohols or cyclodextrins (organic Kosmotropes) or other small molecule drugs by water-driven bioorganic reactions in water. In the water-driven bioorganic reactions, the reagent is stable in water and can modify lysine residues or cysteine residue of a protein at physiological conditions with high yield and fast rate. Proteins and antibodies will be modified by non-natural sugar alcohols. As a result, the efficacy of protein drugs (reduction in aggregation and enzymatic degradation, and increase in blood stream life time) may be improved. ## Claims ### Claim 1 A method of modifying a protein, comprising the step of covalently bonding said protein directly to a squarate molecule that is covalently bonded directly to an organic kosmotrope. ### Claim 2 (depends on 1) The method of claim 1, wherein said organic kosmotrope is a sugar alcohol. ### Claim 3 (depends on 1) The method of claim 1, wherein said organic kosmotrope is a cyclodextrin. ### Claim 4 (depends on 1) The method of claim 1, wherein the protein comprises a small molecule drug. ### Claim 5 (depends on 1) The method of claim 1, wherein the protein comprises an antibody. ### Claim 6 (depends on 3) The method of claim 3, wherein said cyclodextrin comprises alpha-cyclodextrin, beta-cyclodextrin, or gamma cyclodextrin. ### Claim 7 (depends on 1) The method of claim 1, wherein said squarate molecule is a cyclic squarate molecule. ### Claim 8 A stabilized compound, comprising: a protein; and an organic kosmotrope covalently bonded to a squarate molecule that is covalently bonded to said protein. ### Claim 9 (depends on 8) The compound of claim 8, wherein said organic kosmotrope is a cyclodextrin. ### Claim 10 (depends on 8) The compound of claim 8, further comprising a squarate molecule. ### Claim 11 (depends on 8) The compound of claim 8, wherein the protein comprises a small molecule drug. ### Claim 12 (depends on 8) The compound of claim 8, wherein the protein comprises an antibody. ### Claim 13 (depends on 9) The compound of claim 9, wherein said cyclodextrin comprises alpha-cyclodextrin, beta-cyclodextrin, or gamma cyclodextrin. ### Claim 14 (depends on 8) The compound of claim 8, wherein said cyclodextrin is linked with a squarate molecule. ### Claim 15 (depends on 14) The compound of claim 14, wherein said squarate molecule is a cyclic squarate molecule.