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The Screening of Combinatorial Peptide Libraries for Targeting Key Molecules or Protein–Protein Interactions in the NF-κB Pathway

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NF-κB Transcription Factors

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2366))

Abstract

Peptides are emerging as an increasingly dependable class of therapeutics in the treatment of cancer and metabolic and cardiovascular diseases, which are all areas of high interest to the pharmaceutical industry. The global market for peptide therapeutics was valued at about 25 billion USD in 2018 and is estimated to reach 57.2 billion USD by the end of 2027. Here, we describe a method for the screening and deconvolution of combinatorial peptide libraries to discover compounds that target discrete signaling components of the NF-κB pathway. Recently, we used this approach to specifically disrupt the interaction between the JNK-activating kinase, MKK7, and the NF-κB-regulated antiapoptotic factor, GADD45β, in multiple myeloma (MM). We showed that the GADD45β/MKK7 complex is a functionally critical survival module downstream of NF-κB in MM cells and as such provides an attractive therapeutic target to selectively inhibit NF-κB antiapoptotic signaling in cancer cells. By integrating the library screening and deconvolution methods described here with a rational chemical optimization strategy, we developed the first-in-class GADD45β/MKK7 inhibitor, DTP3 (a D-tripeptide), which is now being trialed in MM and diffuse large B-cell lymphoma (DLBCL) patients. The same drug discovery approach may be generally applied to therapeutically target other key components of the NF-κB pathway in cancers beyond MM and DLBCL, as well as in non-malignant NF-κB-driven diseases.

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Acknowledgments

This work was supported in part by Medical Research Council (MRC) Biomedical Catalyst grant MR/L005069/1, Bloodwise project grant 15003, and NIHR Imperial Biomedical Research Centre (BRC) Push for Impact Award WIIS_P81135 to G.F. Infrastructure support for this research was provided in part by the NIHR Imperial BRC. The authors would like to acknowledge and thank Mr. Cristian Ng for his assistance with the literature review.

Conflict of Interest

G.F., L.T., and M.R. are named inventors on patents relating to this research.

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Authors and Affiliations

  1. Centre for Molecular Immunology and Inflammation, Department of Immunology and Inflammation, Imperial College London, London, UK

    Laura Tornatore, Daria Capece & Guido Franzoso

  2. Department of Biotechnological and Applied Clinical Sciences (DISCAB), University of L’Aquila, L’Aquila, Italy

    Daria Capece, Daniela Verzella, Davide Vecchiotti & Francesca Zazzeroni

  3. Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche (CNR), Naples, Italy

    Annamaria Sandomenico & Menotti Ruvo

Authors
  1. Laura Tornatore
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  2. Daria Capece
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  3. Annamaria Sandomenico
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  4. Daniela Verzella
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  5. Davide Vecchiotti
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  6. Francesca Zazzeroni
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  7. Menotti Ruvo
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  8. Guido Franzoso
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Corresponding author

Correspondence to Guido Franzoso .

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Editors and Affiliations

  1. Centre for Molecular Immunology and Inflammation, Department of Immunology and Inflammation, Imperial College London, London, UK

    Guido Franzoso

  2. Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy

    Francesca Zazzeroni

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Tornatore, L. et al. (2021). The Screening of Combinatorial Peptide Libraries for Targeting Key Molecules or Protein–Protein Interactions in the NF-κB Pathway. In: Franzoso, G., Zazzeroni, F. (eds) NF-κB Transcription Factors. Methods in Molecular Biology, vol 2366. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1669-7_21

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  • DOI: https://doi.org/10.1007/978-1-0716-1669-7_21

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1668-0

  • Online ISBN: 978-1-0716-1669-7

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