Site-selective labeling of a lysine residue in human serum albumin

Shigehiro Asano, James T. Patterson, Thomas Gaj, Carlos F. Barbas

Research output: Contribution to journalArticle

Abstract

Conjugation to human serum albumin (HSA) has emerged as a powerful approach for extending the in vivo halflife of many small molecule and peptide/protein drugs. Current HSA conjugation strategies, however, can often yield heterogeneous mixtures with inadequate pharmacokinetics, low efficacies, and variable safety profiles. Here, we designed and synthesized analogues of TAK-242, a small molecule inhibitor of Toll-like receptor 4, that primarily reacted with a single lysine residue of HSA. These TAK-242-based cyclohexene compounds demonstrated robust reactivity, and Lys64 was identified as the primary conjugation site. A bivalent HSA conjugate was also prepared in a site-specific manner. Additionally, HSA-cyclohexene conjugates maintained higher levels of stability both in human plasma and in mice than the corresponding maleimide conjugates. This new conjugation strategy promises to broadly enhance the performance of HSA conjugates for numerous applications.

Original languageEnglish (US)
Pages (from-to)11783-11786
Number of pages4
JournalAngewandte Chemie - International Edition
Volume53
Issue number44
DOIs
StatePublished - Sep 4 2014
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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