An Albumin Sandwich Enhances in Vivo Circulation and Stability of Metabolically Labile Peptides

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Abstract
The effectiveness of numerous molecular drugs is hampered by their poor pharmacokinetics. Different from previous approaches with limited effectiveness, most recently, emerging high-affinity albumin binding moieties (ABMs) for in vivo hitchhiking endogenous albumin opens up an avenue to chaperon small molecules for long-acting therapeutics. Although several FDA approved fatty acids have showed prolonged residence and therapeutic effect, an easy-synthesized, water-soluble and high-efficiency ABM with versatile drug loading ability is extremely needed to improve therapeutic efficacy of short-lived constructs. We herein identified an ideal bivalent Evans blue derivative, denoted as N(tEB)2, as a smart ABM-delivery platform to chaperon short-lived molecules, through both computational modelling screening and efficient synthetic schemes. The optimal N(tEB)2 could reversibly link two molecules of albumin through its two binding heads with a preferable spacer, resulting in significantly extended circulation half-life of a preloaded cargo and water-soluble. Notably, this in situ dimerization of albumin was able to sandwich peptide therapeutics to protect them from proteolysis. As an application, we conjugated N(tEB)2 with exendin-4 for long-acting glucose control in a diabetic mouse model, and it was superior to both previously tested NtEB-exendin-4 (Abextide) and the newly FDA-approved semaglutide, which has been arguably the best commercial weekly formula so far. Hence, this novel albumin binder has excellent clinical potential for next-generation biomimetic drug delivery system.
Funding Information
  • U.S. Department of Health and Human Services (ZIA EB000073)
  • National Natural Science Foundation of China (81871404)

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