Two Birds, One Stone

  • ChemPubSoc Europe Logo
  • Author: Scott Williams
  • Published Date: 08 November 2010
  • Source / Publisher: ChemMedChem/Wiley-VCH
  • Copyright: Wiley-VCH Verlag GmbH & Co. KGaA
thumbnail image: Two Birds, One Stone

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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.


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