Acylated oxyntomodulin peptide analog
Inventors
Yang, Jae-Sung • Lee, Kyung-Seok • Chae, Yu-Na • BAEK, GYE-RIM • Kim, Tae-Hyoung • JUNG, ILL-HUN • RYU, CHAE-LIM • Im, Weon-Bin
Assignees
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Publication Number
US-11713344-B2
Publication Date
2023-08-01
Expiration Date
Abstract
A novel peptide analog of acylated oxyntomodulin and its uses are disclosed. A pharmaceutical composition containing the novel peptide analog is useful and effective for preventing and treating obesity or overweightness, or diabetes accompanied by obesity and overweightness. The peptide analog and a composition containing the peptide analog are superior to those of wild-type oxyntomodulin in dual agonism on GLP-1 and glucagon receptors and longer in vivo half-life. A pharmaceutical composition containing the peptide analog is effective in the treatment of metabolic diseases such as obesity and diabetes mellitus.
Core Innovation
The invention relates to oxyntomodulin peptide analogs comprising an intramolecular cross-link at X19 and X20 within the amino acid sequence His-X17-Gln-Gly-Thr-Phe-Thr-Ser-Asp-X18-Ser-Lys-Tyr-Leu-Asp-X19-Arg-Arg-Ala-X20-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Lys (SEQ ID NO: 53). X17 is Aib, X18 is Z, and X19 and X20 are selected from Asp, Glu, Cys, Hcy, Lys or Orn. The C-terminal amino acid may optionally be amidated, and Z is a modified Lys to which a Z1-Z2 moiety is attached.
The intramolecular cross-link at X19 and X20 forms a cyclic peptide. The cyclic peptide may form either via an amide bond between two residues at X19 and X20, or via a cross-linker bond between residues at X19 and X20. The resulting cyclic peptide includes a lactam ring or a cross-linked ring.
Z is defined as modified Lys where Z1 is Formula (1) and Z2 is Formula (3). One part of Formula (1) is directly bound to a side chain of Lys, and a bond between Z1 and Z2 is defined through specified connection points. The described embodiments include oxyntomodulin peptide analogs having Z modifications and cyclic peptide features.
Claims Coverage
The independent claim coverage centers on one oxyntomodulin peptide analog framework with three inventive features: an intramolecular cross-link at X19 and X20, defined residue selections at X17, X18, X19, and X20 with optional C-terminal amidation, and a modified Lys substituent Z carrying Z1-Z2.
Intramolecular cross-link forming a cyclic peptide ring at X19 and X20
An oxyntomodulin peptide analog comprising an intramolecular cross-link at X19 and X20 that forms a cyclic peptide having a lactam ring formed by an amide bond between two residues at X19 and X20 or a cross-linked ring formed by a cross-linker bond between two residues at X19 and X20.
Defined sequence framework with constrained positions X17, X18, X19, and X20
The peptide analog has the sequence His-X17-Gln-Gly-Thr-Phe-Thr-Ser-Asp-X18-Ser-Lys-Tyr-Leu-Asp-X19-Arg-Arg-Ala-X20-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Lys (SEQ ID NO: 53), wherein X17 is Aib, X18 is Z, and X19 and X20 are selected from Asp, Glu, Cys, Hcy, Lys or Orn.
Modified Lys Z carrying Z1-Z2 moieties via defined bonds
Z is modified Lys to which Z1-Z2 of Formula (1) and Formula (3) is attached, wherein one part of Formula (1) is directly bound to a side chain of Lys and a bond between Z1 and Z2 is defined through specified connection points.
Treating obesity or overweight with the claimed pharmaceutical composition
Treating a subject with obesity or overweight by administering an effective amount of the pharmaceutical composition of a specified dependent claim.
The claim coverage is directed to a defined oxyntomodulin peptide analog in which X19 and X20 form an intramolecular cyclic structure via either a lactam amide bond or a cross-linker bond, while X18 is defined as a modified Lys bearing Z1-Z2 with specified bonding relations. It also includes a therapeutic use claim for obesity or overweight treatment.
Stated Advantages
Improved DPP-IV resistance.
Increased in vivo half-life associated with albumin binding.
GLP-1 and glucagon dual receptor agonism.
Superiority over wild-type oxyntomodulin in dual agonism and longer half-life.
Documented Applications
Treating obesity or overweight by administering an oxyntomodulin peptide analog and/or a pharmaceutical composition including the peptide analog.
Treating non-insulin-dependent diabetes in association with obesity, using the described peptide analogs and pharmaceutical compositions.
Use in metabolic syndrome context is mentioned in the described rationale.
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