期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 53, 期 44, 页码 11783-11786出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201405924
关键词
chemoselectivity; drug conjugates; human serum albumin; lysine labeling; site-specific conjugation
资金
- Skaggs Institute for Chemical Biology
Conjugation to human serum albumin (HSA) has emerged as a powerful approach for extending the in vivo half-life 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.
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