Structural Basis of the Change in the Interaction between Mycophenolic Acid and Subdomain IIA of Human Serum Albumin during Renal Failure

Keishi Yamasaki, Honoka Teshima, Reina Yukizawa, Koki Kuyama, Kenji Tsukigawa, Koji Nishi, Masaki Otagiri, Akito Kawai

研究成果: ジャーナルへの寄稿学術論文査読

4 被引用数 (Scopus)

抄録

Mycophenolic acid (MP) is an active metabolite of mycophenolate mofetil, a widely used immunosuppressive drug. MP normally exhibits high plasma protein binding (97-99%), but its binding rate is decreased in patients with renal insufficiency. This decreased protein binding is thought to be associated with leukopenia, a side effect of MP. In this study, we characterized the change in protein binding of MP in renal failure patients. Our findings indicate that MP binds strongly to subdomain IIA of human serum albumin. X-ray crystallographic data indicated that the isobenzofuran group of MP forms a stacking interaction with Trp214, and the carboxyl group of MP is located at a position that allows the formation of hydrogen bonds with Tyr150, His242, or Arg257. Due to the specific binding of MP to subdomain IIA, MP is thought to be displaced by uremic toxin (3-carboxy-4-methyl-5-propyl-2-furan-propionic acid) and fatty acids (oleate or myristate) that can bind to subdomain IIA, resulting in the decreased plasma protein binding of MP in renal failure.

本文言語英語
ページ(範囲)951-961
ページ数11
ジャーナルJournal of Medicinal Chemistry
66
1
DOI
出版ステータス出版済み - 12-01-2023

All Science Journal Classification (ASJC) codes

  • 分子医療
  • 創薬

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