Controlling plasma protein binding: Structural correlates of interactions of hydrophobic polyamine endotoxin sequestrants with human serum albumin

Thuan B. Nguyen, E. V.K.Suresh Kumar, Diptesh Sil, Stewart J. Wood, Kelly A. Miller, Hemamali J. Warshakoon, Apurba Datta, Sunil A. David

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Hydrophobically substituted polyamine compounds, particularly N-acyl or N-alkyl derivatives of homospermine, are potent endotoxin (lipopolysaccharide) sequestrants. Despite their polycationic nature, the aqueous solubilites are limited owing to the considerable overall hydrophobicity contributed by the long-chain aliphatic substituent, but solubilization is readily achieved in the presence of human serum albumin (HSA). We desired first to delineate the structural basis of lipopolyamine-albumin interactions and, second, to explore possible structure-activity correlates in a well-defined, congeneric series of N-alkyl and -acyl homospermine lead compounds. Fluorescence spectroscopic and isothermal titration calorimetry (ITC) results indicate that these compounds appear to bind to HSA via occupancy of the fatty-acid binding sites on the protein. The acyl and carbamate compounds bind HSA the strongest; the ureido and N-alkyl analogues are significantly weaker, and the branched alkyl compound is weaker still. ITC-derived dissociation constants are weighted almost in their entirety by enthalpic ΔH terms, which is suggestive that the polarizability of the carbonyl groups facilitate, at least in large part, their interactions with HSA. The relative affinities of these lipopolyamines toward HSA is reflected in discernible differences in apparent potencies of LPS-sequestering activity under experimental conditions requiring physiological concentrations of HSA, and also of in vivo pharmacodynamic behavior. These results are likely to be useful in designing analogues with varying pharmacokinetic profiles.

Original languageEnglish (US)
Pages (from-to)1131-1137
Number of pages7
JournalMolecular pharmaceutics
Volume5
Issue number6
DOIs
StatePublished - Dec 1 2008

Keywords

  • Albumin
  • Endotoxin sequestrants
  • Lipopolyamines
  • Plasma protein binding

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    Nguyen, T. B., Kumar, E. V. K. S., Sil, D., Wood, S. J., Miller, K. A., Warshakoon, H. J., Datta, A., & David, S. A. (2008). Controlling plasma protein binding: Structural correlates of interactions of hydrophobic polyamine endotoxin sequestrants with human serum albumin. Molecular pharmaceutics, 5(6), 1131-1137. https://doi.org/10.1021/mp8001123