Partially unfolded proteins efficiently penetrate cell membranes - Implications for oral drug delivery

Sam J. Milstein, Harry Leipold, Donald Sarubbi, Andrea Leone-Bay, Gwen M. Mlynek, Joseph R. Robinson, Marina Kasimova, Ernesto Freire

Research output: Contribution to journalArticlepeer-review


We have previously reported on the biological activity of members of a library of low molecular weight compounds (carriers) that enable the oral delivery of proteins (Milstein, Proceedings of the 1995 Miami Bio/Technology Winter Symposium on Protein Engineering and Structural Biology, IRL Press at Oxford University Press, 1995, p. 13; Leone-Bay et al., J. Med. Chem. 38 (1995) 4263-4269; Leone-Bay et al., J. Med. Chem. 39 (1996) 2571-2578; [1- 3]). When rats or primates are orally administered a solution of carrier and either recombinant human α-interferon (rhIFN), insulin or recombinant human growth hormone (rhGH) significant serum concentrations of the proteins are detectable. The transport activity of these compounds is positively correlated with their structural effects on the protein molecules. Direct measurement of the interaction of these carrier molecules with the proteins indicates that they reversibly destabilize the native state of the molecule favoring a partially unfolded conformation. Apparently these intermediate protein conformations are transport competent and are able to be absorbed through the intestinal tissue and into the bloodstream. Since the measured binding of the carders to the partially unfolded proteins is relatively weak (K(b)=100 M-1) and the systemic activity of the proteins appears to be unaffected, the changes in the structure of the proteins are manifestly reversible.

Original languageEnglish (US)
Pages (from-to)259-267
Number of pages9
JournalJournal of Controlled Release
Issue number1-3
StatePublished - Apr 30 1998


  • Intermediate conformation
  • Molten globule state
  • Passive diffusion
  • T(m) (melting temperature)
  • ΔG (change in Gibbs free energy)

ASJC Scopus subject areas

  • Pharmaceutical Science


Dive into the research topics of 'Partially unfolded proteins efficiently penetrate cell membranes - Implications for oral drug delivery'. Together they form a unique fingerprint.

Cite this