{"id":391,"date":"2015-02-26T12:48:47","date_gmt":"2015-02-26T17:48:47","guid":{"rendered":"https:\/\/research.cbc.osu.edu\/pei.3\/?page_id=391"},"modified":"2022-09-05T21:32:52","modified_gmt":"2022-09-06T01:32:52","slug":"chemical-biology","status":"publish","type":"page","link":"https:\/\/research.cbc.osu.edu\/pei.3\/research\/chemical-biology\/","title":{"rendered":"Macrocyclic Peptides as Protein-Protein Interaction Inhibitors"},"content":{"rendered":"

\nSmall molecules generally require well-defined, hydrophobic binding pockets in their target proteins to achieve high affinity and specificity (Figure 1a). This largely limits small molecules to targeting enzymes, G-protein coupled receptors, and ion channels. Protein-protein interactions (PPIs) usually involve large, flat binding sites, thus representing a challenging class of drug targets for conventional small molecules. This is because small molecules generally do not make enough points of contact with a flat surface (Figure 1b). On the other hand, we (and others) have previously demonstrated that macrocyclic peptides in the molecular-weight range of 500-2000 are capable of binding to flat surfaces with antibody-like affinity and specificity and serve as effective PPI inhibitors (Figure 1c). These macrocycles are 3-5 times larger than conventional small molecules and therefore make more pints of contact with a flat surface.<\/h4>\n
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Figure 1. Comparison of small molecules and macrocycles for target binding. (a) A small-molecule inhibitor is engulfed by the deep binding pocket of a traditional target (e.g., an enzyme or receptor), resulting in high affinity and specificity. (b) Binding of a small molecule to a flat PPI binding site results in low affinity and specificity. (c) A macrocycle engages in many points of contact with a flat PPI binding site and achieves high affinity and specificity.<\/p><\/div>\n

Unfortunately, macrocyclic ligands of the above size range are challenging to design by rational approaches. We therefore choose to chemically synthesize large combinatorial libraries of macrocyclic peptides 108<\/sup> different compounds) and then rapidly screen them for binding to a protein of interest (Figure 2).<\/h4>\n
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Figure 2. Scheme showing the combinatorial synthesis of cyclic peptides in the OBOC format and screening for binding against a fluorescently labeled protein.<\/p><\/div>\n

We have developed novel methods to synthesize and screen peptide-encoded monocyclic [1] and bicyclic peptide libraries [2] on spatially segregated microbeads, in which each bead displays a unique cyclic (or bicyclic) peptide on its surface and a linear peptide of the same sequence as an encoding tag inside the bead (Figure 3).<\/h4>\n
\"\"<\/a>

Figure 3. Macrocyclic peptide libraries in the one bead-two compound (OBTC) format, in which each bead displays a cyclic (a) or bicyclic peptide (b) on its surface and a linear peptide of identical sequence in its interior as an encoding tag.<\/p><\/div>\n

After a positive hit is isolated, the structure of the macrocycle is determined by sequencing the encoding tag inside the bead by a partial Edman degradation-mass spectrometry (PED-MS) method [3]. Some examples of macrocyclic peptide ligands identified from our libraries are illustrated in Figure 4 [4-7].<\/h4>\n
\"\"<\/a>

Figure 4. Representative macrocyclic peptide ligands identified from OBTC libraries.<\/p><\/div>\n

Future research in this area includes:<\/h4>\n

1) Optimization of previous library hits (e.g., inhibitors against calcineurin, K-Ras, NEMO, \uf062-catenin, and PDZ domains) to improve their potency, selectivity, stability, and solubility
\n2) Screening libraries against additional disease-modifying proteins<\/h4>\n

<\/h3>\n
\n

Key Publications:<\/h3>\n
    \n
  1. Joo, S. H., Xiao, Q., Ling, Y., Gopishetty, B., and Pei, D. (2006) High-throughput sequence determination of cyclic peptide library members by partial Edman degradation\/mass spectrometry. Am. Chem. Soc. 128<\/em>, 13000-13009.<\/a><\/li>\n
  2. Lian, W., Upadhyaya, P., Rhodes, C. A., Liu, Y., and Pei, D. (2013) Screening Bicyclic Peptide Libraries for Protein\u2212Protein Interaction Inhibitors: Discovery of a Tumor Necrosis Factor-\u03b1 J. Am. Chem. Soc. 135<\/em>, 11990-11995.<\/a><\/li>\n
  3. Thakkar, A., Wavreille, A.-S., and Pei, D. (2006) Traceless capping agent for peptide sequencing by partial Edman degradation and mass spectrometry. Chem. 78<\/em>, 5935-5939.<\/a><\/li>\n
  4. Liu, T.; Liu, Y.; Kao, H.-Y.; Pei, D. (2010) Membrane Permeable Cyclic Peptidyl Inhibitors against Human Peptidylprolyl Isomerase Pin1. Med. Chem. 53<\/em>, 2494-2501.<\/a><\/li>\n
  5. Liu, T., Qian, Z., Xiao, Q., and Pei, D. (2011) High-Throughput Screening of One-Bead-One-Compound Libraries: Identification of Cyclic Peptidyl Inhibitors against Calcineurin\/NFAT Interaction. ACS Comb. Sci<\/em>. 13<\/em>, 537-546.<\/a><\/li>\n
  6. Wu, X., Upadhyaya, P., Villalona-Calero, M. A., Briesewitz, R., and Pei, D. (2013) Inhibition of Ras-effector interactions by cyclic peptides. Chem. Commun<\/em>. 4<\/em>, 378-382.<\/a><\/li>\n
  7. Upadhyaya, P., Qian, Z., Habir, N. A. A., and Pei, D. (2014) Direct Ras Inhibitors Identified from a Structurally Rigidified Bicyclic Peptide Library. Tetrahedron 70<\/em>, 7714-7720.<\/a><\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    Small molecules generally require well-defined, hydrophobic binding pockets in their target proteins to achieve high affinity and specificity (Figure 1a). This largely limits small molecules to targeting enzymes, G-protein coupled receptors, and ion channels. Protein-protein interactions (PPIs) usually involve large, flat binding sites, thus representing a challenging class of drug targets for conventional small molecules.<\/p>\n

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