Tuning the Diels–Alder Reaction for Bioconjugation to Maleimide Drug-Linkers,Bioconjugate Chemistry

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Tuning the Diels–Alder Reaction for Bioconjugation to Maleimide Drug-Linkers
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-06-22 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00320
Andre H. St. Amant ₁ , Daniel Lemen ₂ , Stelios Florinas ₂ , Shenlan Mao ₃ , Christine Fazenbaker ₃ , Haihong Zhong ₃ , Herren Wu ₂ , Changshou Gao ₂ , R. James Christie ₂ , Javier Read de Alaniz ₁

Affiliation

The thiol–maleimide linkage is widely used for antibody–drug conjugate (ADC) production; however, conjugation of maleimide–drugs could be improved by simplified procedures and reliable conjugate stability. Here, we report the evaluation of electron-rich and cyclic dienes that can be appended to antibodies and reacted with maleimide-containing drugs through the Diels–Alder (DA) reaction. Drug conjugation is fast and quantitative due to reaction acceleration in water, and the linkage is more stable in serum than in the corresponding thiol–maleimide adduct with the same drug. ADCs produced using the DA reaction (DAADCs) are effective in vitro and in vivo, demonstrating the utility of this reaction in producing effective biotherapeutics. Given the large number of commercially available maleimide compounds, this conjugation approach could be readily applied to the production of a wide range of antibody (or protein) conjugates.

中文翻译：

调整Diels-Alder反应与马来酰亚胺药物接头的生物缀合

巯基-马来酰亚胺键被广泛用于抗体-药物偶联物（ADC）的生产；然而，通过简化程序和可靠的结合稳定性，可以改善马来酰亚胺-药物的结合。在这里，我们报告了对富电子和环状二烯的评估，这些二烯可以附加到抗体上，并通过Diels-Alder（DA）反应与含马来酰亚胺的药物反应。由于在水中的反应加速，药物结合快速而定量，并且与相同药物的相应硫醇-马来酰亚胺加合物相比，血清中的键合更稳定。使用DA反应产生的ADC（DAADC）在体外和体内均有效，证明了该反应在产生有效生物治疗剂中的效用。鉴于有大量的市售马来酰亚胺化合物，

更新日期：2018-06-22

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