Abnormally high levels of nitric oxide (NO) have been associated in certain cases with tumor growth. In their efforts to address this, a team led by Walter Fast, University of Texas at Austin, USA, set out to develop a single drug that blocks NO production by inhibiting two different enzyme targets. One target is NO synthase, the direct source of NO, and the other is DDAH-1, which degrades an endogenous inhibitor of NO synthase.

Fast and colleagues used a click chemistry mediated activity probe to gauge a series of dual-targeted inhibitors for potency within cultured cells. The most potent of the series was characterized in detail by X-ray crystallography and calorimetry to elucidate its interactions with the DDAH-1 active site. Their study is a combination of cell-based and in vitro work that dissects the contribution of an unusual covalent reversible bond to a compound’s potency, and provides valuable information for the development of new NO-blocking drugs.

• Characterization of C-Alkyl Amidines as Bioavailable Covalent Reversible Inhibitors of Human DDAH-1
  M. Lluis, Y. Wang, A. F. Monzingo, W. Fast, J. D. Robertus,
  ChemMedChem 2011, 6(01).
  DOI: 10.1002/cmdc.201000392