Methyltetrazine-PEG6-maleimide
Methyltetrazine-PEG6-maleimide is a heterobifunctional, PEG-based linker designed for PROTAC and targeted protein degradation workflows that require efficient, bioorthogonal conjugation. Structurally, it combines a methyltetrazine moiety for rapid inverse-electron-demand Diels–Alder reactivity with trans-cyclooctene or related strained alkenes, together with a terminal maleimide that selectively reacts with thiol groups on cysteine-containing ligands or engineered protein domains. The PEG6 spacer provides a flexible, hydrophilic separation between the two functional handles, helping to reduce steric interference and improve conjugation efficiency and subsequent ternary-complex formation. In PROTAC design, this linker enables modular assembly: one partner can be functionalized via the thiol-reactive maleimide, while the second partner can be introduced through tetrazine-mediated click chemistry, allowing controlled stoichiometry and rapid synthesis of degraders. Its practical value lies in simplifying linker installation under mild conditions and supporting systematic structure–activity studies in targeted degradation research.
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* For research and manufacturing use only. Not for human or clinical use.
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Methyltetrazine-PEG6-maleimide is a bifunctional PROTAC linker designed to connect a tetrazine-based recognition handle with a thiol-reactive maleimide for efficient assembly of targeted degradation constructs. Its PEG spacer provides conformational flexibility and improved aqueous compatibility, which can help maintain productive ternary complex formation. The combination of a tetrazine moiety and a maleimide electrophile enables modular synthesis and site-selective conjugation strategies. Detailed structural and reactivity considerations are provided below.
Structure: The linker contains a methyltetrazine unit conjugated to a PEG-based hydrophilic spacer and a terminal maleimide electrophile. It features heteroaromatic nitrogen-rich functionality, an alkene within the maleimide ring, and ether linkages in the PEG chain, supporting water solubility and stable linker behavior.
Reactivity: The maleimide group undergoes rapid thiol–maleimide Michael addition with cysteine- or mercapto-bearing ligands under mildly basic aqueous conditions, forming a stable thioether. The methyltetrazine handle can participate in inverse-electron-demand Diels–Alder reactions with strained dienes (commonly trans-cyclooctene or related motifs) to enable bioorthogonal ligation. Typical workflows use buffered aqueous solvents and avoid competing thiols that can quench maleimide.
* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C1V1 = C2V2
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