Maleimide–thiol adducts stabilized through stretching
NATURE CHEMISTRY(2019)
摘要
Maleimide–thiol reactions are widely used to produce protein–polymer conjugates for therapeutics. However, maleimide–thiol adducts are unstable in vivo or in the presence of thiol-containing compounds because of the elimination of the thiosuccinimide linkage through a retro-Michael reaction or thiol exchange. Here, using single-molecule force spectroscopy, we show that applying an appropriate stretching force to the thiosuccinimide linkage can considerably stabilize the maleimide–thiol adducts, in effect using conventional mechanochemistry of force-accelerated bond dissociation to unconventionally stabilize an adjacent bond. Single-molecule kinetic analysis and bulk structural characterizations suggest that hydrolysis of the succinimide ring is dominant over the retro-Michael reaction through a force-dependent kinetic control mechanism, and this leads to a product that is resistant to elimination. This unconventional mechanochemical approach enabled us to produce stable polymer–protein conjugates by simply applying a mechanical force to the maleimide–thiol adducts through mild ultrasonication. Our results demonstrate the great potential of mechanical force for stimulating important productive chemical transformations.
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关键词
Polymer chemistry,Single-molecule biophysics,Chemistry/Food Science,general,Analytical Chemistry,Organic Chemistry,Physical Chemistry,Inorganic Chemistry,Biochemistry
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