Identification of specific inhibitors of MutS and MutL homolog function

This invention includes 1) methods for testing an agent for the ability to inhibit MutSβ, by forming an assay that includes the agent, MutLα and MutSβ, and evaluating interaction between MutLα and MutSβ in the assay and 2) a means for and testing the agent for the ability to inhibit the interaction between MutLα and MutSα by forming an assay including the agent, MutLα and MutSα, and evaluating interaction between MutLα and MutSα in the assay.

These methods will allow the identification of agents having the ability to specifically inhibit the interaction between MutLα and MutSβ. Identification of these agents may be used to develop structurally related agents that can then be tested by the methods of the invention for the ability to specifically inhibit the interaction between MutLα and MutSβ. It is envisioned that agents having the ability to specifically inhibit the interaction between MutLα and MutSβ could be useful in treating individuals having or at risk for developing deleterious conditions associated with MutSβ activity, e.g., neurological disorders caused by the expansion of (CAG)n repeats.

The methods of the invention will also allow the identification of agents having the ability to specifically inhibit the interaction between MutLα, and MutSα. Such agents may be useful as research tools in further studies of interactions of proteins involved in mismatch repair.

This invention also provides a kit for screening agents for the ability to inhibit the interaction between MutLα and MutSα or MutSβ that includes MutLα, MutSα and/or MutSβ, and a linear heteroduplex DNA substrate or a linear homoduplex DNA control attached to a solid support through one end of the substrate or control. Suitable DNA substrates contain a MutSα- or MutSβ-recognizable mismatch.

Duke File (IDF) Number

T-003399

Inventor(s)

  • Modrich, Paul
  • Iyer, Ravi
  • Pluciennik, Anna
  • Tsai, Miaw-Sheue

Patents

    • Patent Number: 8,623,600
    • Title: METHODS AND COMPOSITIONS FOR IDENTIFYING INHIBITORS OF MUTS-ALPHA OR MUTS-BETA INTERACTION WITH MUTL-ALPHA
    • Country: United States of America

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College

School of Medicine (SOM)