Human serum albumin-based design of a diflunisal prodrug

Feng Yang, Zhi Yuan Ma, Yao Zhang, Guo Qing Li, Mei Li, Jiang Ke Qin, Oksana Lockridge, Hong Liang

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

The cyclooxygenase-2 inhibitor, diflunisal, is used in the clinic for its anti-inflammatory activity. About 99% of a dose of diflunisal is unavailable for reaction with the target enzyme, because diflunisal strongly binds to human serum albumin (HSA). To reduce the binding affinity of diflunisal to albumin, we designed and synthesized the prodrug acetyldiflunisal. The crystal structure of HSA complexed with fatty acid and acetyldiflunisal revealed that acetyldiflunisal binds to the IIA subdomain and that upon binding, it acetylates lysine 199. Mass spectrometry confirmed that acetyldiflunisal acetylates Lys199. The acetylated albumin had twofold weaker binding affinity for diflunisal as demonstrated by fluorescence quenching. Reduced binding affinity means that diflunisal is more easily released from acetylated albumin into the circulation. Therefore, lower doses of acetyldiflunisal compared to diflunisal will be required. Taken together, our results not only provide a template for design of HSA-based prodrugs, but also pave the way toward more effective use of diflunisal in the clinic.

Original languageEnglish (US)
Pages (from-to)549-554
Number of pages6
JournalEuropean Journal of Pharmaceutics and Biopharmaceutics
Volume84
Issue number3
DOIs
StatePublished - Aug 1 2013

Fingerprint

Diflunisal
Prodrugs
Serum Albumin
Albumins
Cyclooxygenase 2 Inhibitors
Lysine
Mass Spectrometry
Anti-Inflammatory Agents
Fatty Acids
Fluorescence
O-acetyldiflunisal

Keywords

  • Acetylation
  • Acetyldiflunisal
  • Crystal structure
  • Lysine 199 of albumin
  • Prodrug design

ASJC Scopus subject areas

  • Biotechnology
  • Pharmaceutical Science

Cite this

Yang, F., Ma, Z. Y., Zhang, Y., Li, G. Q., Li, M., Qin, J. K., ... Liang, H. (2013). Human serum albumin-based design of a diflunisal prodrug. European Journal of Pharmaceutics and Biopharmaceutics, 84(3), 549-554. https://doi.org/10.1016/j.ejpb.2013.01.013

Human serum albumin-based design of a diflunisal prodrug. / Yang, Feng; Ma, Zhi Yuan; Zhang, Yao; Li, Guo Qing; Li, Mei; Qin, Jiang Ke; Lockridge, Oksana; Liang, Hong.

In: European Journal of Pharmaceutics and Biopharmaceutics, Vol. 84, No. 3, 01.08.2013, p. 549-554.

Research output: Contribution to journalArticle

Yang, Feng ; Ma, Zhi Yuan ; Zhang, Yao ; Li, Guo Qing ; Li, Mei ; Qin, Jiang Ke ; Lockridge, Oksana ; Liang, Hong. / Human serum albumin-based design of a diflunisal prodrug. In: European Journal of Pharmaceutics and Biopharmaceutics. 2013 ; Vol. 84, No. 3. pp. 549-554.
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