{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:03:55Z","timestamp":1760123035899,"version":"3.37.3"},"reference-count":64,"publisher":"Portland Press Ltd.","issue":"4","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,8,28]]},"abstract":"<jats:p>The proprotein convertase subtilisin\/kexin type 9 (PCSK9) regulates plasma LDL cholesterol levels by binding to the liver LDL receptor (LDLR) and promoting its degradation. Therefore, PCSK9 has become a compelling new therapeutic target for lipid lowering and the prevention of cardiovascular disease. PCSK9 contains two regions of conformational flexibility, the N-terminal regions of the prodomain and of the catalytic domain. The recognition that the latter region, the so-called P\u2032 helix, is able to transition from an \u03b1-helical to a disordered state gave rise to new strategies to develop small molecule inhibitors of PCSK9 for lipid lowering. In the ordered state the P\u2032 helix is buried in a groove of the PCSK9 catalytic domain located next to the main LDLR binding site. The transition to a disordered state leaves the groove site vacated and accessible for compounds to antagonize LDLR binding. By use of a groove-directed phage display strategy we were able to identify several groove-binding peptides. Based on structural information of PCSK9-peptide complexes, a minimized groove-binding peptide was generated and utilized as an anchor to extend towards the adjacent main LDLR binding site, either by use of a phage-displayed peptide extension library, or by appending organic moieties to yield organo-peptides. Both strategies led to antagonists with pharmacologic activities in cell-based assays. The intricate bipartite mechanism of the potent organo-peptide inhibitors was revealed by structural studies, showing that the core peptide occupies the N-terminal groove, while the organic moiety interacts with the LDLR binding site to create antagonism. These findings validate the PCSK9 groove as an attractive target site and should inspire the development of a new class of small molecule antagonists of PCSK9.<\/jats:p>","DOI":"10.1042\/bst20190672","type":"journal-article","created":{"date-parts":[[2020,8,14]],"date-time":"2020-08-14T15:14:01Z","timestamp":1597418041000},"page":"1323-1336","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Regions of conformational flexibility in the proprotein convertase PCSK9 and design of antagonists for LDL cholesterol lowering"],"prefix":"10.1042","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0975-4402","authenticated-orcid":false,"given":"Daniel","family":"Kirchhofer","sequence":"first","affiliation":[{"name":"Department of Early Discovery Biochemistry, Genentech Inc., South San Francisco, CA 94080, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel J.","family":"Burdick","sequence":"additional","affiliation":[{"name":"Department of Discovery Chemistry, Genentech Inc., South San Francisco, CA 94080, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas J.","family":"Skelton","sequence":"additional","affiliation":[{"name":"Department of Discovery Chemistry, Genentech Inc., South San Francisco, CA 94080, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingnan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Early Discovery Biochemistry, Genentech Inc., South San Francisco, CA 94080, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Ultsch","sequence":"additional","affiliation":[{"name":"Department of Structural Biology, Genentech Inc., South San Francisco, CA 94080, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2020,8,14]]},"reference":[{"key":"2021111916034265900_BST-2019-0672CC1","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1097\/HCO.0000000000000517","article-title":"Proprotein convertase subtilisin\/kexin type 9: from genetics to clinical trials","volume":"33","year":"2018","journal-title":"Curr. Opin. Cardiol."},{"key":"2021111916034265900_BST-2019-0672CC2","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1038\/ng1161","article-title":"Mutations in PCSK9 cause autosomal dominant hypercholesterolemia","volume":"34","year":"2003","journal-title":"Nat. Genet."},{"key":"2021111916034265900_BST-2019-0672CC3","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/ng1509","article-title":"Low LDL cholesterol in individuals of african descent resulting from frequent nonsense mutations in PCSK9","volume":"37","year":"2005","journal-title":"Nat. Genet."},{"key":"2021111916034265900_BST-2019-0672CC4","doi-asserted-by":"publisher","first-page":"1264","DOI":"10.1056\/NEJMoa054013","article-title":"Sequence variations in PCSK9, low LDL, and protection against coronary heart disease","volume":"354","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"2021111916034265900_BST-2019-0672CC5","doi-asserted-by":"publisher","first-page":"928","DOI":"10.1073\/pnas.0335507100","article-title":"The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation","volume":"100","year":"2003","journal-title":"Proc. Natl Acad. Sci. U.S.A."},{"key":"2021111916034265900_BST-2019-0672CC6","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1161\/CIRCRESAHA.114.301621","article-title":"PCSK9: a key modulator of cardiovascular health","volume":"114","year":"2014","journal-title":"Circ. Res."},{"key":"2021111916034265900_BST-2019-0672CC7","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1038\/nrd3699","article-title":"The biology and therapeutic targeting of the proprotein convertases","volume":"11","year":"2012","journal-title":"Nat. Rev. Drug Discov."},{"key":"2021111916034265900_BST-2019-0672CC8","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1038\/nsmb1235","article-title":"Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia","volume":"14","year":"2007","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2021111916034265900_BST-2019-0672CC9","doi-asserted-by":"publisher","first-page":"14604","DOI":"10.1073\/pnas.0703402104","article-title":"The self-inhibited structure of full-length PCSK9 at 1.9 A reveals structural homology with resistin within the C-terminal domain","volume":"104","year":"2007","journal-title":"Proc. Natl Acad. Sci. U.S.A."},{"key":"2021111916034265900_BST-2019-0672CC10","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1016\/j.str.2007.04.004","article-title":"The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol","volume":"15","year":"2007","journal-title":"Structure"},{"key":"2021111916034265900_BST-2019-0672CC11","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/S0006-291X(67)80055-X","article-title":"On the size of the active site in proteases. I. Papain","volume":"27","year":"1967","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021111916034265900_BST-2019-0672CC12","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1074\/jbc.M808363200","article-title":"Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants","volume":"284","year":"2009","journal-title":"J. Biol. Chem."},{"key":"2021111916034265900_BST-2019-0672CC13","doi-asserted-by":"publisher","first-page":"2018","DOI":"10.1002\/pro.3019","article-title":"Point mutations at the catalytic site of PCSK9 inhibit folding, autoprocessing, and interaction with the LDL receptor","volume":"25","year":"2016","journal-title":"Protein Sci."},{"key":"2021111916034265900_BST-2019-0672CC14","doi-asserted-by":"publisher","first-page":"1820","DOI":"10.1073\/pnas.0712064105","article-title":"Molecular basis for LDL receptor recognition by PCSK9","volume":"105","year":"2008","journal-title":"Proc. Natl Acad. Sci. U.S.A."},{"key":"2021111916034265900_BST-2019-0672CC15","doi-asserted-by":"publisher","first-page":"1671","DOI":"10.1042\/BST20140273","article-title":"Protein moonlighting: a new factor in biology and medicine","volume":"42","year":"2014","journal-title":"Biochem. Soc. Trans."},{"key":"2021111916034265900_BST-2019-0672CC16","doi-asserted-by":"publisher","first-page":"2043","DOI":"10.1016\/j.bbamcr.2017.05.013","article-title":"New intracellular activities of matrix metalloproteinases shine in the moonlight","volume":"1864","year":"2017","journal-title":"Biochim. Biophys. Acta. Mol. Cell Res."},{"key":"2021111916034265900_BST-2019-0672CC17","doi-asserted-by":"publisher","first-page":"1927","DOI":"10.3389\/fimmu.2018.01927","article-title":"Holding all the CARDs: how MALT1 controls CARMA\/CARD-dependent signaling","volume":"9","year":"2018","journal-title":"Front. Immunol."},{"key":"2021111916034265900_BST-2019-0672CC18","doi-asserted-by":"publisher","first-page":"103877","DOI":"10.1016\/j.cellimm.2018.11.001","article-title":"Ubiquitination and phosphorylation of the CARD11-BCL10-MALT1 signalosome in T cells","volume":"340","year":"2019","journal-title":"Cell. Immunol."},{"key":"2021111916034265900_BST-2019-0672CC19","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1016\/j.str.2013.04.003","article-title":"Crystal structures of the viral protease Npro imply distinct roles for the catalytic water in catalysis","volume":"21","year":"2013","journal-title":"Structure"},{"key":"2021111916034265900_BST-2019-0672CC20","doi-asserted-by":"publisher","first-page":"e1003704","DOI":"10.1371\/journal.ppat.1003704","article-title":"The structure of classical swine fever virus N(pro): a novel cysteine autoprotease and zinc-binding protein involved in subversion of type I interferon induction","volume":"9","year":"2013","journal-title":"PLoS Pathog."},{"key":"2021111916034265900_BST-2019-0672CC21","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/bs.aivir.2015.03.002","article-title":"The molecular biology of pestiviruses","volume":"93","year":"2015","journal-title":"Adv. Virus res."},{"key":"2021111916034265900_BST-2019-0672CC22","doi-asserted-by":"publisher","first-page":"18602","DOI":"10.1074\/jbc.M702027200","article-title":"Binding of proprotein convertase subtilisin\/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation","volume":"282","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2021111916034265900_BST-2019-0672CC23","doi-asserted-by":"publisher","first-page":"1300","DOI":"10.1038\/embor.2011.205","article-title":"Mechanistic implications for LDL receptor degradation from the PCSK9\/LDLR structure at neutral pH","volume":"12","year":"2011","journal-title":"EMBO Rep."},{"key":"2021111916034265900_BST-2019-0672CC24","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1038\/s41467-017-00568-7","article-title":"Heparan sulfate proteoglycans present PCSK9 to the LDL receptor","volume":"8","year":"2017","journal-title":"Nat. Commun."},{"key":"2021111916034265900_BST-2019-0672CC25","doi-asserted-by":"publisher","first-page":"1787","DOI":"10.1194\/jlr.M018093","article-title":"Role of the C-terminal domain of PCSK9 in degradation of the LDL receptors","volume":"52","year":"2011","journal-title":"J. Lipid Res."},{"key":"2021111916034265900_BST-2019-0672CC26","doi-asserted-by":"publisher","first-page":"13045","DOI":"10.1073\/pnas.0806312105","article-title":"Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor","volume":"105","year":"2008","journal-title":"Proc. Natl Acad. Sci. U.S.A."},{"key":"2021111916034265900_BST-2019-0672CC27","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1056\/NEJMoa1615664","article-title":"Evolocumab and clinical outcomes in patients with cardiovascular disease","volume":"376","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"2021111916034265900_BST-2019-0672CC28","doi-asserted-by":"publisher","first-page":"2097","DOI":"10.1056\/NEJMoa1801174","article-title":"Alirocumab and cardiovascular outcomes after acute coronary syndrome","volume":"379","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"2021111916034265900_BST-2019-0672CC29","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/j.jacc.2018.10.039","article-title":"Alirocumab reduces total nonfatal cardiovascular and fatal events: the ODYSSEY OUTCOMES trial","volume":"73","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"2021111916034265900_BST-2019-0672CC30","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1161\/CIRCRESAHA.115.304351","article-title":"Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing","volume":"115","year":"2014","journal-title":"Circ. Res."},{"key":"2021111916034265900_BST-2019-0672CC31","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1056\/NEJMoa1609243","article-title":"A highly durable RNAi therapeutic inhibitor of PCSK9","volume":"376","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"2021111916034265900_BST-2019-0672CC32","doi-asserted-by":"publisher","first-page":"e114469","DOI":"10.1371\/journal.pone.0114469","article-title":"Peptide-based anti-PCSK9 vaccines - an approach for long-term LDLc management","volume":"9","year":"2014","journal-title":"PLoS ONE"},{"key":"2021111916034265900_BST-2019-0672CC33","doi-asserted-by":"publisher","first-page":"e2001882","DOI":"10.1371\/journal.pbio.2001882","article-title":"Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain","volume":"15","year":"2017","journal-title":"PLoS Biol."},{"key":"2021111916034265900_BST-2019-0672CC34","doi-asserted-by":"publisher","first-page":"1362","DOI":"10.1016\/j.chembiol.2016.08.016","article-title":"A small-Molecule anti-secretagogue of PCSK9 targets the 80S ribosome to inhibit PCSK9 protein translation","volume":"23","year":"2016","journal-title":"Cell Chem. Biol."},{"key":"2021111916034265900_BST-2019-0672CC35","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1056\/NEJMoa1615758","article-title":"Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol","volume":"376","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"2021111916034265900_BST-2019-0672CC36","doi-asserted-by":"publisher","first-page":"9736","DOI":"10.1039\/C6OB01642A","article-title":"Disrupting the PCSK9\/LDLR protein-protein interaction by an imidazole-based minimalist peptidomimetic","volume":"14","year":"2016","journal-title":"Org. Biomol. Chem."},{"key":"2021111916034265900_BST-2019-0672CC37","doi-asserted-by":"publisher","first-page":"1350","DOI":"10.1111\/bcp.12738","article-title":"Antisense-mediated reduction of proprotein convertase subtilisin\/kexin type 9 (PCSK9): a first-in-human randomized, placebo-controlled trial","volume":"80","year":"2015","journal-title":"Br. J. Clin. Pharmacol."},{"key":"2021111916034265900_BST-2019-0672CC38","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1074\/jbc.M113.514067","article-title":"Identification of a small peptide that inhibits PCSK9 protein binding to the low density lipoprotein receptor","volume":"289","year":"2014","journal-title":"J. Biol. Chem."},{"key":"2021111916034265900_BST-2019-0672CC39","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1016\/j.ejmech.2015.01.022","article-title":"LDL-R promoting activity of peptides derived from human PCSK9 catalytic domain (153\u2013421): design, synthesis and biochemical evaluation","volume":"92","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"2021111916034265900_BST-2019-0672CC40","doi-asserted-by":"publisher","first-page":"29931","DOI":"10.1038\/srep29931","article-title":"Lupin peptides modulate the protein-protein interaction of PCSK9 with the low density lipoprotein receptor in HepG2 cells","volume":"6","year":"2016","journal-title":"Sci. Rep."},{"key":"2021111916034265900_BST-2019-0672CC41","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1016\/j.chembiol.2013.11.014","article-title":"Design and synthesis of truncated EGF-A peptides that restore LDL-R recycling in the presence of PCSK9 in vitro","volume":"21","year":"2014","journal-title":"Chem. Biol."},{"key":"2021111916034265900_BST-2019-0672CC42","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1124\/jpet.114.214221","article-title":"Pharmacologic profile of the adnectin BMS-962476, a small protein biologic alternative to PCSK9 antibodies for low-density lipoprotein lowering","volume":"350","year":"2014","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2021111916034265900_BST-2019-0672CC43","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1124\/jpet.117.246652","article-title":"Generation and characterization of a novel small biologic alternative to proprotein convertase subtilisin\/Kexin type 9 (PCSK9) antibodies, DS-9001a, albumin binding domain-Fused anticalin protein","volume":"365","year":"2018","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2021111916034265900_BST-2019-0672CC44","doi-asserted-by":"publisher","first-page":"115344","DOI":"10.1016\/j.bmc.2020.115344","article-title":"A small molecule inhibitor of PCSK9 that antagonizes LDL receptor binding via interaction with a cryptic PCSK9 binding groove","volume":"28","year":"2020","journal-title":"Bioorg. Med. Chem."},{"key":"2021111916034265900_BST-2019-0672CC45","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1016\/j.jmb.2018.11.025","article-title":"Identification of a helical segment within the intrinsically disordered region of the PCSK9 prodomain","volume":"431","year":"2019","journal-title":"J. Mol. Biol."},{"key":"2021111916034265900_BST-2019-0672CC46","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1529\/biophysj.106.094045","article-title":"Intrinsic disorder and functional proteomics","volume":"92","year":"2007","journal-title":"Biophys. J."},{"key":"2021111916034265900_BST-2019-0672CC47","doi-asserted-by":"publisher","first-page":"6589","DOI":"10.1021\/cr400525m","article-title":"Classification of intrinsically disordered regions and proteins","volume":"114","year":"2014","journal-title":"Chem. Rev."},{"key":"2021111916034265900_BST-2019-0672CC48","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.1186\/1471-2164-9-S2-S1","article-title":"The unfoldomics decade: an update on intrinsically disordered proteins","volume":"9","year":"2008","journal-title":"BMC Genomics"},{"key":"2021111916034265900_BST-2019-0672CC49","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.atherosclerosis.2006.12.035","article-title":"Genetic variants in PCSK9 in the Japanese population: rare genetic variants in PCSK9 might collectively contribute to plasma LDL cholesterol levels in the general population","volume":"196","year":"2008","journal-title":"Atherosclerosis"},{"key":"2021111916034265900_BST-2019-0672CC50","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1016\/j.atherosclerosis.2012.04.006","article-title":"Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemia","volume":"223","year":"2012","journal-title":"Atherosclerosis"},{"key":"2021111916034265900_BST-2019-0672CC51","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1161\/01.ATV.0000204337.81286.1c","article-title":"Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy","volume":"26","year":"2006","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2021111916034265900_BST-2019-0672CC52","doi-asserted-by":"publisher","first-page":"3480","DOI":"10.1111\/j.1742-4658.2008.06495.x","article-title":"PCSK9 is phosphorylated by a Golgi casein kinase-like kinase ex vivo and circulates as a phosphoprotein in humans","volume":"275","year":"2008","journal-title":"FEBS J."},{"key":"2021111916034265900_BST-2019-0672CC53","doi-asserted-by":"publisher","first-page":"1619","DOI":"10.1016\/j.cell.2015.05.028","article-title":"A single kinase generates the majority of the secreted phosphoproteome","volume":"161","year":"2015","journal-title":"Cell"},{"key":"2021111916034265900_BST-2019-0672CC54","doi-asserted-by":"publisher","first-page":"48865","DOI":"10.1074\/jbc.M409699200","article-title":"NARC-1\/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol","volume":"279","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2021111916034265900_BST-2019-0672CC55","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1038\/nsmb.3453","article-title":"Discovery of a cryptic peptide-binding site on PCSK9 and design of antagonists","volume":"24","year":"2017","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2021111916034265900_BST-2019-0672CC56","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1021\/acschembio.9b00899","article-title":"Design of organo-peptides as bipartite PCSK9 antagonists","volume":"15","year":"2020","journal-title":"ACS Chem. Biol."},{"key":"2021111916034265900_BST-2019-0672CC57","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"46","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"2021111916034265900_BST-2019-0672CC58","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1038\/nrd.2016.253","article-title":"From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors","volume":"16","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"2021111916034265900_BST-2019-0672CC59","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1038\/nm.3048","article-title":"ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets","volume":"19","year":"2013","journal-title":"Nat. Med."},{"key":"2021111916034265900_BST-2019-0672CC60","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1007\/s12551-019-00570-x","article-title":"Protein-protein interaction modulators: advances, successes and remaining challenges","volume":"11","year":"2019","journal-title":"Biophys. Rev."},{"key":"2021111916034265900_BST-2019-0672CC61","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1042\/EBC20170028","article-title":"Current perspectives in fragment-based lead discovery (FBLD)","volume":"61","year":"2017","journal-title":"Essays Biochem."},{"key":"2021111916034265900_BST-2019-0672CC62","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1038\/nature03579","article-title":"An inhibitor of Bcl-2 family proteins induces regression of solid tumours","volume":"435","year":"2005","journal-title":"Nature"},{"key":"2021111916034265900_BST-2019-0672CC63","doi-asserted-by":"publisher","first-page":"3262","DOI":"10.1039\/D0CS00102C","article-title":"Peptidomimetic toolbox for drug discovery","volume":"49","year":"2020","journal-title":"Chem. Soc. Rev."},{"key":"2021111916034265900_BST-2019-0672CC64","doi-asserted-by":"publisher","first-page":"959","DOI":"10.3390\/molecules23040959","article-title":"Using peptidomimetics and constrained peptides as valuable tools for inhibiting protein\u2013protein interactions","volume":"23","year":"2018","journal-title":"Molecules"}],"container-title":["Biochemical Society Transactions"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article-pdf\/48\/4\/1323\/891992\/bst-2019-0672c.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article-pdf\/48\/4\/1323\/891992\/bst-2019-0672c.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T16:26:40Z","timestamp":1637339200000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article\/48\/4\/1323\/226077\/Regions-of-conformational-flexibility-in-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,14]]},"references-count":64,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,8,14]]},"published-print":{"date-parts":[[2020,8,28]]}},"URL":"https:\/\/doi.org\/10.1042\/bst20190672","relation":{},"ISSN":["0300-5127","1470-8752"],"issn-type":[{"type":"print","value":"0300-5127"},{"type":"electronic","value":"1470-8752"}],"subject":[],"published":{"date-parts":[[2020,8,14]]}}}