Covalent binding of cefotaxime to human serum albumin.

Toyo’oka, Toshimasa; Sano, Akimitsu; Kuriki, Takeo; Suzuki, Nobuo

doi:10.1248/bpb1978.6.139

Cited by 3 publications

(1 citation statement)

References 4 publications

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“…HSA has 59 lysine residues and can be used as a scaffold for the covalent modification of drugs. In addition, some compounds with electrophilic properties, such as β-lactam antibiotics, have been reported to react with lysine residues present on the surface of HSA [10]. Lysine-modified albumins with an electrically charged boron cluster have been developed for boron neutron capture therapy, in these studies modified albumins were used as a carrier of boron to tumor tissue [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Functionalization of Human Serum Albumin by Tyrosine Click

Obara

Nakane

Fujimura

et al. 2021

IJMS

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Human serum albumin (HSA) is a promising drug delivery carrier. Although covalent modification of Cys34 is a well-established method, it is desirable to develop a novel covalent modification method that targets residues other than cysteine to introduce multiple functions into a single HSA molecule. We developed a tyrosine-selective modification of HSA. Three tyrosine selective modification methods, hemin-catalyzed, horseradish peroxidase (HRP)-catalyzed, and laccase-catalyzed reactions were performed, and the modification efficiencies and modification sites of the modified HSAs obtained by these methods were evaluated and compared. We found that the laccase-catalyzed method could efficiently modify the tyrosine residue of HSA under mild reaction conditions without inducing oxidative side reactions. An average of 2.2 molecules of functional groups could be introduced to a single molecule of HSA by the laccase method. Binding site analysis using mass spectrometry suggested Y84, Y138, and Y401 as the main modification sites. Furthermore, we evaluated binding to ibuprofen and found that, unlike the conventional lysine residue modification, the inhibition of drug binding was minimal. These results suggest that tyrosine-residue selective chemical modification is a promising method for covalent drug attachment to HSA.

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Section: Introductionmentioning

confidence: 99%

Functionalization of Human Serum Albumin by Tyrosine Click

Obara

Nakane

Fujimura

et al. 2021

IJMS

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Site‐Selective Labeling of a Lysine Residue in Human Serum Albumin

et al. 2014

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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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Site‐Selective Labeling of a Lysine Residue in Human Serum Albumin

Asano¹,

Patterson²,

Gaj³

et al. 2014

Angew Chem Int Ed

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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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Covalent binding of cefotaxime to human serum albumin.

Cited by 3 publications

References 4 publications

Functionalization of Human Serum Albumin by Tyrosine Click

Functionalization of Human Serum Albumin by Tyrosine Click

Site‐Selective Labeling of a Lysine Residue in Human Serum Albumin

Site‐Selective Labeling of a Lysine Residue in Human Serum Albumin

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