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Dissection, Optimization, and Structural Analysis of a Covalent Irreversible DDAH1 Inhibitor.

Gayle Burstein-Teitelbaum1, Joyce A V Er1, Arthur F Monzingo2

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Researchers developed a potent inhibitor, Cl-NIL, for dimethylarginine dimethylaminohydrolase-1 (DDAH1), an enzyme controlling nitric oxide production. This novel inhibitor shows high selectivity and effectiveness in cellular models.

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Area of Science:

  • Biochemistry
  • Enzymology
  • Pharmacology

Background:

  • Dimethylarginine dimethylaminohydrolase-1 (DDAH1) regulates endogenous nitric oxide (NO) production.
  • Inhibiting DDAH1 offers a strategy to control NO levels.
  • Understanding DDAH1 inhibition mechanisms is crucial for therapeutic development.

Purpose of the Study:

  • To design and characterize novel, potent inhibitors of DDAH1.
  • To investigate the structure-activity relationships of DDAH1 inhibitors.
  • To evaluate the efficacy and selectivity of a new DDAH1 inhibitor in cellular models.

Main Methods:

  • Conceptual dissection of a known DDAH1 inactivator into fragments.
  • Synthesis and characterization of DDAH1 inhibitor analogues.
  • Enzyme kinetics, including KI, kinact, and second-order rate constants.
  • Activity-based protein profiling in HEK293T cells.
  • X-ray crystallography to determine the inhibitor-DDAH1 complex structure.

Main Results:

  • A novel inhibitor, N5-(1-imino-2-chloroethyl)-l-lysine (Cl-NIL), was synthesized and found to be highly potent (KI = 0.19 μM, kinact = 0.22 min-1).
  • Cl-NIL exhibits a high second-order inactivation rate constant (1.9 × 104 M-1 s-1) and >100,000-fold selectivity for DDAH1 over arginase.
  • Inhibition of DDAH1 in HEK293T cells was observed (IC50 = 10 μM) with minimal cytotoxicity (ED50 = 118 μM).
  • X-ray crystallography revealed specific interactions between Cl-NIL and DDAH1.

Conclusions:

  • Fragment-based dissection of covalent inactivators is an effective strategy for designing potent enzyme inhibitors.
  • Cl-NIL is a highly potent and selective DDAH1 inhibitor with potential therapeutic applications.
  • The structural insights provide a basis for further optimization of DDAH1-targeted therapies.