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Related Concept Videos

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Development of a Backbone Cyclic Peptide Library as Potential Antiparasitic Therapeutics Using Microwave Irradiation
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Influence of Macrocyclization Strategies on DNA-Encoded Cyclic Peptide Libraries.

Hanqing Zhao1,2, Xue Li3, Xueyu Yao3

  • 1State Key Laboratory of Drug Research Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Zhang Jiang Hi-Tech Park, Pudong, Shanghai 201203, China.

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|August 1, 2025
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Summary

DNA-encoded libraries (DELs) enabled discovery of cyclic peptides. Researchers explored linker effects on DEL selections against MDM2 and GIT1, identifying potent inhibitors like cmp-10 and cmp-17 with validated binding mechanisms.

Keywords:
DNA-encoded library technologyGIT1MDM2cyclic peptidedisulfidemacrocyclizationthioether

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Area of Science:

  • Medicinal Chemistry
  • Chemical Biology
  • Drug Discovery

Background:

  • DNA-encoded libraries (DELs) are powerful tools for discovering small molecule binders.
  • Developing macrocyclization methods compatible with DELs is crucial for cyclic peptide discovery.
  • Understanding how linker variations impact DEL selection outcomes is essential for optimizing hit identification.

Purpose of the Study:

  • To investigate the influence of different cyclic linkers on DEL selection outcomes.
  • To identify and validate cyclic peptide inhibitors against protein targets MDM2 and GIT1.
  • To elucidate the binding mechanism of identified compounds.

Main Methods:

  • Construction and screening of eight distinct DNA-encoded sublibraries.
  • Selection against protein targets MDM2 and GIT1.
  • On-DNA and off-DNA validation of selected hits, including inhibition and dissociation constant measurements.
  • Isothermal Titration Calorimetry (ITC) experiments with mutant proteins.

Main Results:

  • Screening against MDM2 yielded hits with structural similarity patterns, including potent inhibitor cmp-10 (Ki = 11 nM).
  • Selection against GIT1 produced distinct enrichment patterns, with validated binder cmp-17 (Kd = 1.22 μM) showing specific binding.
  • ITC experiments provided mechanistic insights into how cmp-17 disrupts the GIT1-β-PIX interaction.

Conclusions:

  • Cyclic linker choice significantly influences DEL selection outcomes for different protein targets.
  • DEL technology can successfully identify potent and specific cyclic peptide inhibitors.
  • The identified compounds and mechanistic data advance the field of cyclic peptide drug discovery.