METHOD OF OBTAINING ABM-TGIRIS-ABU IMMUNOSUPPRESSOR PEPTIDE LABALED BY GD ION Russian patent published in 2019 - IPC C07K7/06 A61K38/08 A61K51/08 

FIELD: medicine; chemistry.

SUBSTANCE: invention relates to the field of medical chemistry, immunology and neurobiology, and is aimed at developing a new agent for the treatment of multiple sclerosis, corresponding to class of biologically active substance – conjugate of immunosuppressive peptide Abu-TGIRIS-Abu with chelating agent – diethylenetriaminopentaacetic acid (DTPA), which is in the form of a coordination complex with the Gd³⁺ ion. In the framework of the present invention, a method for the preparation of the Gd³⁺ complex salt with DTPA-Lys-diglycolate-Ahx-Abu-TGIRIS-Abu-NH₂ was proposed, where DTPA denotes diethylenetriaminopentaacetic acid, Ahx denotes aminohexanoic acid, Abu denotes α-aminobutyric acid, comprising the following steps: (1) to Abu-TGIRIS-Abu peptide synthesized by the solid-phase method using MBHA-polystyrene as a carrier, without removing it from the polymer substrate, aminohexanoic acid is added to obtain the Ahx-Abu-TGIRIS-Abu-NH₂ peptide, connected via residue α-aminobutyric acid to the amino group of MBHA-modified polystyrene, (2) get (S)-9-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)ethyl)-6-(2-(tert-butoxy)-2-oxoethyl)-10-(tert-butoxycarbonyl)-2,2-dimethyl-4,16-dioxo-3,18-dioxa-6,9,15-triazicosan-20-olic acid, (3) to the Ahx-Abu-TGIRIS-Abu peptide attached to the amino group of MBHA-modified polystyrene through the residue α-aminobutyric acid, add the condensing mixture in the form of a solution of (S)-9-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)ethyl)-6-(2-(tert-butoxy)-2-oxoethyl)-10-(tert-butoxycarbonyl)-2,2-dimethyl-4,16-dioxo-3,18-dioxa-6,9,15-triazicosan-20-olic acid in dimethylformamide, (4) carry out the removal of the protective groups and the peptide from the substrate, (5) receive the complex salt Gd³⁺ with DTPA-Lys-diglycolate-Ahx-Abu-TGIRIS-Abu-NH₂ by reaction of the modified peptide with the Gd³⁺ salt. Conjugate can be used as a means of visualizing lymphocytes that are potentially involved in autoimmune damage to the myelin sheaths of the CNS in vivo using paramagnetic resonance or for selective destruction of such lymphocytes using X-ray induced thermoablation in vitro and in vivo. Linker structure eliminates the risk of disruption of the binding of the peptide ligand to the surface receptor of lymphocytes due to steric difficulties associated with the large size and rigidity of the coordination complex DTPA with Gd³⁺ ions.

EFFECT: method allows to obtain an Abu-TGIRIS-Abu peptide conjugate with DTPA articulated via a long moderately hydrophilic flexible linker.

1 cl, 24 dwg, 1 ex