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Macrocyclization and multimerization of universal peptides and proteins using diels-alder cycloaddition reactions

A macrocyclic compound, reaction technology, applied in the direction of peptides, peptide libraries, specific peptides, etc., can solve the problem of chemical reactions not yet site-specific and stable.

Pending Publication Date: 2022-03-11
UNIVERSITY OF CHICAGO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these properties overlap with those expected for selective modification of biomolecules, this chemistry has not been applied to site-specific stabilization of peptides or proteins.

Method used

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  • Macrocyclization and multimerization of universal peptides and proteins using diels-alder cycloaddition reactions
  • Macrocyclization and multimerization of universal peptides and proteins using diels-alder cycloaddition reactions
  • Macrocyclization and multimerization of universal peptides and proteins using diels-alder cycloaddition reactions

Examples

Experimental program
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Effect test

Embodiment 1

[0191] A. Diels-Alder cyclized peptides

[0192] A series of Diels-Alder cyclization (DAC) peptides with turn and loop motifs were synthesized, including anti-migratory RGD peptides, whose analogs are undergoing clinical testing in oncology. Model peptides of various lengths and sequences were synthesized containing orthogonally protected cysteine ​​(tBuS-) and lysine (Mmt-) side chains, the former always at the i position and the latter at the i+ 4. i+5 and i+7 positions. Sequential on-resin cysteine ​​deprotection and hexadiene alkylation were quantitatively performed using 1-bromo-2,4-hexadiene ( figure 1 , figure 2 , Figure 5 A). The corresponding diene-containing amino acid Fmoc-Cys(2,4-hexadiene)-OH was also synthesized, which is compatible with direct incorporation by SPPS ( figure 1 , image 3 ). Subsequent on-resin deprotection and acylation of lysine using N-maleimide-glycine on the RGD model peptide resulted in the formation of two distinct peaks (1 and 1...

Embodiment 2

[0240] This example demonstrates that Diels-Alder cyclization is compatible and contributes to intramolecular disulfide bond stabilization.

[0241] Atrial natriuretic peptide (ANP) is a peptide hormone released by cells of the atrium in response to regulating sodium levels and blood volume. ANP has low pharmacological stability, which limits its use. Recent evidence suggests that it could be used clinically to inhibit cytokine release syndrome during CAR-T therapy for cancer.

[0242] ANP sequence and potential DAC design:

[0243] ANP-WT: SCFGGRMDRIGAQSGLGCNSF (SEQ ID NO: 6), which can be acetylated on the N-terminal serine

[0244] DAC-ANP: SCFGGRX1DRIGAQX2GLGCNSF (SEQ ID NO:7), which can be acetylated on the N-terminal serine

[0245] X1 / X2=K(mal) / K(acr) / K(cpd)...(dienophile)

[0246] C(hex) / S(hex) / C(cpd) / A(fur)…(diene)

[0247] Figure 23A and Figure 23B Representative amino acid side chains, N-terminal or C-terminal functionalized with dienes and dienophiles are ...

Embodiment 3

[0254] This example demonstrates the synthesis of Lys(cpd).

[0255] Cyclopentadiene containing lysine amino acid was synthesized by acylation of protected lysine with 1.5 equivalents of cyclopentadiene NHS ester with 1 equivalent of DIPEA, and then used in 25% piperidine in DMF for Fmoc group to protect. see Figure 29 and Figure 30 .

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Abstract

The present disclosure provides macrocyclic and macrobicyclic peptides having a secondary structure that is more stable than the corresponding acyclic peptides. The macrocyclic and macrobicyclic peptides are formed from peptides having complementary reactive side chain moieties that form adducts.

Description

[0001] Cross References to Related Applications [0002] This patent application claims the benefit of U.S. Provisional Patent Application No. 62 / 831,484, filed April 9, 2019, and U.S. Provisional Patent Application No. 62 / 894,478, filed August 30, 2019, each of which is incorporated herein by reference in its entirety middle. [0003] Statement Regarding Federally Sponsored Research or Development [0004] This invention was made with Government support under Grant Nos. GM008720 and GM128199 awarded by the National Institutes of Health. The government has certain rights in this invention. [0005] Electronic submissions incorporated by reference [0006] Incorporated herein in its entirety by reference is the computer readable nucleotide / amino acid sequence listing filed herewith and identified as follows: A 5112 word file entitled "749097SequenceListing.TXT" created on April 9, 2020 Section ASCII (text) files. [0007] Background of the invention [0008] Peptides repres...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K1/10C07K7/64C40B40/10
CPCC40B40/10C07K1/10C07K7/06C07K7/08C07K14/001C07K1/04C07K7/50
Inventor 雷蒙德·E·莫勒林杰弗里·E·蒙哥马利
Owner UNIVERSITY OF CHICAGO
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