TY - JOUR
T1 - Site-selective labeling of a lysine residue in human serum albumin
AU - Asano, Shigehiro
AU - Patterson, James T.
AU - Gaj, Thomas
AU - Barbas, Carlos F.
N1 - Publisher Copyright:
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA Weinheim.
PY - 2014/9/4
Y1 - 2014/9/4
N2 - 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.
AB - 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.
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U2 - 10.1002/anie.201405924
DO - 10.1002/anie.201405924
M3 - Article
C2 - 25196737
AN - SCOPUS:84918820121
SN - 1433-7851
VL - 53
SP - 11783
EP - 11786
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 44
ER -