Calorimetric studies of the interaction between the insulin-enhancing drug candidate bis(maltolato)oxovanadium(IV) (BMOV) and human serum apo-transferrin.

Abstract

Bis(maltolato)oxovanadium(IV) (BMOV), and its ethylmaltol analog, bis(ethylmaltolato)oxovanadium(IV) (BEOV), are candidate insulin-enhancing agents for the treatment of type 2 diabetes mellitus; in mid-2008, BEOV advanced to phase II clinical testing. The interactions of BMOV and its inorganic congener, vanadyl sulfate (VOSO(4)), with human serum apo-transferrin (hTf) were investigated using differential scanning calorimetry (DSC). Addition of BMOV or VOSO(4) to apo-hTf resulted in an increase in thermal stability of both the C- and N-lobes of transferrin as a result of binding to either vanadyl compound. A series of DSC thermograms of hTf solutions containing different molar ratios of BMOV and VOSO(4) were used to determine binding constants; at 25 degrees C the binding constants of BMOV to the C- and N-lobes of apo-hTf were found to be 3 (+/-1)x10(5) and 1.8 (+/-0.7)x10(5)M(-1), respectively. The corresponding values for VOSO(4) were 1.7 (+/-0.3)x10(5) and 7 (+/-2)x10(4)M(-1). The results show that the vanadium species initially presented as either BMOV or VOSO(4) had similar affinities for human serum transferrin due to oxidation of solvated vanadyl(IV) prior to complexation to transferrin. Binding of metavanadate (VO(3)(-)) was confirmed by DSC and isothermal titration calorimetry (ITC) experiments of the interaction between sodium metavanadate (NaVO(3)) and hTf.

• Authors: Abdol-Khalegh Bordbar, A Louise Creagh, Fakhrossadat Mohammadi, Charles A Haynes, Chris Orvig
• Journal: Journal of inorganic biochemistry (J Inorg Biochem) Vol. 103 Issue 4 Pg. 643-7 (Apr 2009) ISSN: 1873-3344 [Electronic] United States
• PMID: 19056126 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoproteins
• Hypoglycemic Agents
• Insulin
• Pyrones
• Transferrin
• apotransferrin
• bis(maltolato)oxovanadium(IV)
• Vanadates

Topics

• Apoproteins (blood, chemistry, metabolism)
• Calorimetry
• Drug Synergism
• Humans
• Hydrogen-Ion Concentration
• Hypoglycemic Agents (chemistry, pharmacology)
• Insulin (metabolism)
• Kinetics
• Pyrones (chemistry, pharmacology)
• Transferrin (chemistry, metabolism)
• Vanadates (chemistry, pharmacology)