{"id":1536,"date":"2022-11-10T05:55:53","date_gmt":"2022-11-10T10:55:53","guid":{"rendered":"https:\/\/prismbiolab.com\/?p=1536"},"modified":"2022-11-15T00:22:27","modified_gmt":"2022-11-15T05:22:27","slug":"cyclic-peptides-not-just-a-goldmine-for-ppi-drug-discovery","status":"publish","type":"post","link":"https:\/\/prismbiolab.com\/ja\/cyclic-peptides-not-just-a-goldmine-for-ppi-drug-discovery\/","title":{"rendered":"Cyclic peptides: Not Just A Goldmine for PPI Drug Discovery"},"content":{"rendered":"<p>Transition from a macrocyclic peptide to a small molecule with the desired activity is still a huge challenge in drug discovery and development. Here is an interesting strategy \u201cPeptide-to-Small Molecule\u201d developed by Shionogi Pharma Co., Ltd., where small molecules are generated by pharmacophore-guided <i>de novo<\/i> design from macrocyclic peptides.1<\/p>\n<p>Macrocyclic peptides are goldmines for drug discovery. Numerous efforts have been made to dig out a lead or a candidate from the treasure trove of natural peptides for decades. However, macrocyclic peptides have, in general, low membrane permeability and orally bioavailable drug development have been a serious issue. Simple macrocyclic peptide modification (<i>N<\/i>-methylation, for instance) would raise the permeability but it is difficult to achieve high affinity and permeability at the same time.\u00a0 From the viewpoint of medicinal chemistry, lead optimization stage has a serious issue due to the limitation of synthetic methodology in the presence of a number of functional groups. It is fascinating if a high-affinity macrocyclic peptide could easily be replaced by a small molecule without significant loss of the affinity and the potency.<\/p>\n<p>Shionogi Pharma\u2019s \u201cPeptide-to-Small Molecule\u201d strategy is a combination of <i>in vitro<\/i> screening for high-affinity macrocyclic peptide and <i>de novo<\/i> design of small molecules. They selected peptide display for affinity selection to realize a high-throughput screening (HTS). Shionogi Pharma has nonexclusive technology license agreement with PeptiDream Inc., which has non-natural, synthetic macrocyclic peptide library technology called PDPS (Peptide Discovery Platform System). HTS <i>in vitro<\/i> screening system obviously matches Shionogi Pharma\u2019s needs to utilize PDPS technology for peptidomimetic drug discovery.<\/p>\n<p>Their <i>de novo<\/i> small molecule design is guided by pharmacophores, which are figured out by structure-based X-ray co-crystallographic analysis of a target protein and the high-affinity macrocyclic peptide. Potential small molecules would be identified by <i>in silico<\/i> technologies (i.e., SBDD, virtual screening) and these molecules is readily be designed for synthesis and further optimization. Therefore, their approach is not based on a particular peptide structure but a series of interactions for high-affinity.<\/p>\n<p>The potential of \u201cPeptide-to-Small Molecules\u201d was demonstrated by targeting nicotinamide <i>N<\/i>-methyltransferase (NNMT). A macrocyclic peptide was identified by cell-free <i>in vitro<\/i> assay (IC<sub>50<\/sub> = 0.10\u03bcM) without any activity on a cell-based assay. Application of their own strategy not only raised cell-free affinity (IC<sub>50<\/sub> = 0.0011\u03bcM) but also gave cell-based activity (IC<sub>50<\/sub> = 0.40\u03bcM). It is obvious that \u201cPeptide-to-Small Molecules\u201d is a novel option for peptide-based drug discovery.<\/p>\n<p>Thing are changing. There is a review published in 2013, titled \u201cFrom Peptides to Small Molecules: An Intriguing but Intricated Way to New Drugs\u201d in Current Medicinal Chemistry.2 Strategies from peptides to small molecule was a \u201cIntriguing but Intricated\u201d stage but now it\u2019s becoming reasonable.<\/p>\n<p>Our PepMetics<sup>\u00ae<\/sup> is a different approach from \u201cPeptide-to-Small Molecules\u201d for PPI drug discovery. PepMetics<sup>\u00ae<\/sup> is basically structural mimetics: mimicking the backbone and the side chains of a peptide or protein. Shionogi\u2019s strategy is mechanistic mimetics: focusing on the pharmacophore. Their strategy is powerful when X-ray co-crystallographic structure is available while our approach have a potential to realize \u201cPeptide-to-Small Molecule\u201d without a co-crystal. Structural mimetics library has a great potential to find a lead without any information of target-peptide interaction. PepMetics<sup>\u00ae<\/sup> also provides mechanistic mimetics approach by pharmacophore-guided SBDD and virtual screening. Simultaneous application of <i>both<\/i> would also be interesting for rapid discovery of PPI drugs, wouldn\u2019t it?<\/p>\n<p>An age of peptidomimetics is coming. Let\u2019s get together to open up new possibility for PPI drug discovery and development by the use of macrocyclic peptides and peptidomimetic technologies.<\/p>\n<ol>\n<li aria-level=\"1\"><a href=\"https:\/\/pubs.acs.org\/doi\/10.1021\/acs.jmedchem.2c00919\" target=\"_blank\" rel=\"noopener\">https:\/\/pubs.acs.org\/doi\/10.1021\/acs.jmedchem.2c00919<\/a><\/li>\n<li aria-level=\"1\"><a href=\"http:\/\/www.eurekaselect.com\/article\/54464\" target=\"_blank\" rel=\"noopener\">http:\/\/www.eurekaselect.com\/article\/54464<\/a><\/li>\n<\/ol>","protected":false},"excerpt":{"rendered":"<p>Transition from a macrocyclic peptide to a small molecule with the desired activity is still a huge challenge in drug discovery and development. Here is an interesting strategy \u201cPeptide-to-Small Molecule\u201d developed by Shionogi Pharma Co., Ltd., where small molecules are generated by pharmacophore-guided de novo design from macrocyclic peptides.1 Macrocyclic peptides are goldmines for drug [&hellip;]<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[18],"tags":[],"class_list":["post-1536","post","type-post","status-publish","format-standard","hentry","category-blog"],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.3 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Cyclic peptides: Not Just A Goldmine for PPI Drug Discovery - PRISM BioLab<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/prismbiolab.com\/ja\/cyclic-peptides-not-just-a-goldmine-for-ppi-drug-discovery\/\" \/>\n<meta property=\"og:locale\" content=\"ja_JP\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Cyclic peptides: Not Just A Goldmine for PPI Drug Discovery - PRISM BioLab\" \/>\n<meta property=\"og:description\" content=\"Transition from a macrocyclic peptide to a small molecule with the desired activity is still a huge challenge in drug discovery and development. Here is an interesting strategy \u201cPeptide-to-Small Molecule\u201d developed by Shionogi Pharma Co., Ltd., where small molecules are generated by pharmacophore-guided de novo design from macrocyclic peptides.1 Macrocyclic peptides are goldmines for drug [&hellip;]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/prismbiolab.com\/ja\/cyclic-peptides-not-just-a-goldmine-for-ppi-drug-discovery\/\" \/>\n<meta property=\"og:site_name\" content=\"PRISM BioLab\" \/>\n<meta property=\"article:published_time\" content=\"2022-11-10T10:55:53+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2022-11-15T05:22:27+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/prismbiolab.com\/wp-content\/uploads\/2022\/08\/career-collage.jpeg\" \/>\n\t<meta property=\"og:image:width\" content=\"1122\" \/>\n\t<meta property=\"og:image:height\" content=\"1097\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"author\" content=\"vera\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:image\" content=\"https:\/\/prismbiolab.com\/wp-content\/uploads\/2022\/08\/career-collage.jpeg\" \/>\n<meta name=\"twitter:label1\" content=\"\u57f7\u7b46\u8005\" \/>\n\t<meta name=\"twitter:data1\" content=\"vera\" \/>\n\t<meta name=\"twitter:label2\" content=\"\u63a8\u5b9a\u8aad\u307f\u53d6\u308a\u6642\u9593\" \/>\n\t<meta name=\"twitter:data2\" content=\"3\u5206\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\\\/\\\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\\\/\\\/prismbiolab.com\\\/cyclic-peptides-not-just-a-goldmine-for-ppi-drug-discovery\\\/#article\",\"isPartOf\":{\"@id\":\"https:\\\/\\\/prismbiolab.com\\\/cyclic-peptides-not-just-a-goldmine-for-ppi-drug-discovery\\\/\"},\"author\":{\"name\":\"vera\",\"@id\":\"https:\\\/\\\/prismbiolab.com\\\/#\\\/schema\\\/person\\\/c39849cfa45a5eee95d62d3998e14ac9\"},\"headline\":\"Cyclic peptides: Not Just A Goldmine for PPI Drug Discovery\",\"datePublished\":\"2022-11-10T10:55:53+00:00\",\"dateModified\":\"2022-11-15T05:22:27+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\\\/\\\/prismbiolab.com\\\/cyclic-peptides-not-just-a-goldmine-for-ppi-drug-discovery\\\/\"},\"wordCount\":600,\"publisher\":{\"@id\":\"https:\\\/\\\/prismbiolab.com\\\/#organization\"},\"articleSection\":[\"Blog\"],\"inLanguage\":\"ja\"},{\"@type\":\"WebPage\",\"@id\":\"https:\\\/\\\/prismbiolab.com\\\/cyclic-peptides-not-just-a-goldmine-for-ppi-drug-discovery\\\/\",\"url\":\"https:\\\/\\\/prismbiolab.com\\\/cyclic-peptides-not-just-a-goldmine-for-ppi-drug-discovery\\\/\",\"name\":\"Cyclic peptides: Not Just A Goldmine for PPI Drug Discovery - 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