Ligand Design with Accelerated Disulfide Formation with Serum Albumin to Extend Blood Retention

We proposed a novel ligand for the interaction with human serum albumin (HSA) to extend the blood half-life of small molecular weight therapeutics. The ligand features an alkyl chain and an activated disulfide to allow binding to the hydrophobic pockets of HSA and the formation of disulfide to Cys34 of HSA, thereby minimizing the initial renal clearance. The dual nature of the ligand-HSA bonding was expected to give the ligand long blood retention. After 1 min of mixing with HSA, the ligand showed higher binding (1.7 times) than that of a control ligand (containing only activated disulfide). After intravenous injection to mice, the ligand half-lives were 1.6 and 9.2 times longer than those of control ligands with the active disulfide alone and with the alkyl chain alone, respectively. The proposed ligand has the potential to act as a platform for extending the half-life of small therapeutics in vivo.

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Publication Details

Journal
ACS Medicinal Chemistry Letters
Published
2024-12-16
DOI
https://doi.org/10.1021/acsmedchemlett.4c00503
Primary Topic
Protein Interaction Studies and Fluorescence Analysis
Type
article
Field-Weighted Citation Impact
0.00

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article

Ligand Design with Accelerated Disulfide Formation with Serum Albumin to Extend Blood Retention

Takeshi Mori, Atsushi Shimada, Khanh Quoc Phan, Yoshiki Katayama et al.
ACS Medicinal Chemistry Letters
Protein Interaction Studies and Fluorescence Analysis
article

Ligand Design with Accelerated Disulfide Formation with Serum Albumin to Extend Blood Retention

Takeshi Mori, Atsushi Shimada, Khanh Quoc Phan, Yoshiki Katayama, Takeshi Hirota, Song Qi, Ichiro Ieiri, Noriko Yutsudo, Takahiro Muraoka, Takeru Nose, Akihiro Kishimura, Yuichi Tsuchiya, Keitaro Suyama, Jedidiah Canarejo, Zixuan Liu
article en

Abstract

We proposed a novel ligand for the interaction with human serum albumin (HSA) to extend the blood half-life of small molecular weight therapeutics. The ligand features an alkyl chain and an activated disulfide to allow binding to the hydrophobic pockets of HSA and the formation of disulfide to Cys34 of HSA, thereby minimizing the initial renal clearance. The dual nature of the ligand-HSA bonding was expected to give the ligand long blood retention. After 1 min of mixing with HSA, the ligand showed higher binding (1.7 times) than that of a control ligand (containing only activated disulfide). After intravenous injection to mice, the ligand half-lives were 1.6 and 9.2 times longer than those of control ligands with the active disulfide alone and with the alkyl chain alone, respectively. The proposed ligand has the potential to act as a platform for extending the half-life of small therapeutics in vivo.

ACS Medicinal Chemistry LettersVol. 16(1)
Kyushu University (JP), Kyushu University Hospital (JP), Tokyo University of Agriculture and Technology (JP)
Japan Agency for Medical Research and Development, Center for Clinical and Translational Research
Openalex Percentile: Top 80%
Protein Interaction Studies and Fluorescence Analysis
DOIOpen Access PDFOpenAlex
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