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 journalArticlepeer-review

23 Scopus citations


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
Issue number3
StatePublished - Aug 2013


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

ASJC Scopus subject areas

  • Biotechnology
  • Pharmaceutical Science


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