Exendin-4 analogue pegylated with polyethylene glycol or derivative thereof, preparation method thereof, and pharmaceutical composition for preventing or treating diabetes, containing same as active ingredient
Inventors
Lee, Sung Kwon • Kim, Won Bae • Lee, Seulki • Kim, Tae Hyung
Assignees
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Publication Number
US-10406230-B2
Publication Date
2019-09-10
Expiration Date
Abstract
The present disclosure relates to an exendin-4 analog PEGylated with polyethylene glycol or a derivative thereof, a preparation method, and a pharmaceutical composition for prevention or treatment of diabetes containing the same as an active ingredient. According to the present invention, the yield of an exendin-4 analog can be increased via the selective PEGylation by using exendin-4 in which a cysteine is introduced into #40 site of the C-terminal, and treatment effect of medications can be increased, so that the exendin-4 analog can be usefully applied as a composition for prevention or treatment of diseases caused by insulin hypersecretion.
Core Innovation
The invention provides an exendin-4 analogue comprising SEQ ID NO:2 with a cysteine added to the c-terminal end of SEQ ID NO:2 and PEGylated with a trimer of polyethylene glycol (PEG) or a methoxy-activated derivative of PEG. The trimer comprises a spacer formed of a polyethylene glycol or a methoxy-activated derivative thereof, with the spacer connected to the terminal cysteine. The spacer has a molecular weight between 3 kDa and 10 kDa.
The disclosed subject matter further specifies that the trimer of PEG, or the methoxy-activated derivative of PEG, comprising the spacer has a molecular weight greater than 20 and up to 50 kDa. The PEGylation is selective through the use of the terminal cysteine and the spacer-linked trimer structure.
The disclosed subject matter states improved selective PEGylation yield and an enhanced therapeutic effect for diabetes-related, insulin hypersecretion-related diseases. Reported comparisons in the partial content indicate higher C40-specific PEGylation yield versus lower yields for non-specific or N-terminal PEGylation, and increased GLP-1 receptor binding affinity for the C40-PEG construct versus comparative PEGylation positions.
The invention also describes pharmaceutical composition and formulation options for treating diabetes-related indications, including type 1 diabetes and type 2 diabetes and insulin hypersecretion-related diseases. The partial content states longer low-blood-glucose sustainability in db/db mice for trimeric PEG constructs.
Claims Coverage
The independent claim defines the core composition by combining an exendin-4 analogue (SEQ ID NO:2) with a C-terminal cysteine and trimeric PEG (or methoxy-activated PEG) featuring a spacer linked to the terminal cysteine, with molecular-weight ranges that constrain both the spacer and the overall PEG-trimer construct. The independent claim therefore contains multiple inventive feature constraints, including the specific PEG-trimer architecture, the connection to the C-terminal cysteine, and defined molecular-weight windows.
C-terminal cysteine on exendin-4 analogue SEQ ID NO:2
An exendin-4 analogue comprising SEQ ID NO:2 and a cysteine (Cys) added to the c-terminal end of SEQ ID NO:2.
Trimeric PEG or methoxy-activated derivative PEGylation
PEGylated with a trimer of polyethylene glycol (PEG) or a methoxy-activated derivative of PEG, wherein the trimer comprises a polyethylene glycol or a methoxy-activated derivative thereof spacer.
Spacer connected to terminal cysteine with spacer molecular weight range
The spacer is connected to the terminal cysteine, and wherein the spacer has a molecular weight between 3 kDa and 10 kDa.
Overall PEG-trimer molecular weight range
The trimer of PEG, or the methoxy-activated derivative of PEG, comprising the spacer has a molecular weight greater than 20 and up to 50 kDa.
Across the independent claim, the inventive concept is centered on an exendin-4 analogue (SEQ ID NO:2) bearing a C-terminal cysteine that enables PEGylation using a trimeric PEG (or methoxy-activated PEG) architecture with a spacer linked to the terminal cysteine, where both spacer and overall construct are constrained by specified molecular-weight ranges.
Stated Advantages
Improved selective PEGylation yield for C40-specific PEGylation versus non-specific or N-terminal PEGylation.
Enhanced therapeutic effect for diabetes/insulin hypersecretion-related diseases.
Increased GLP-1 receptor binding affinity for the C40-PEG construct compared with comparative PEGylation positions.
Longer low-blood-glucose sustainability in db/db mice for trimeric PEG constructs.
Documented Applications
Treatment of diabetes, including type 1 diabetes and type 2 diabetes, and insulin hypersecretion-related diseases, using pharmaceutical compositions comprising the disclosed exendin-4 analogue and PEGylated constructs.
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