{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T18:09:23Z","timestamp":1788804563563,"version":"build-2803163510"},"reference-count":32,"publisher":"American Chemical Society (ACS)","issue":"19","license":[{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100003359","name":"Generalitat Valenciana","doi-asserted-by":"publisher","award":["PROMETEO 2021\/03"],"award-info":[{"award-number":["PROMETEO 2021\/03"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci?n","doi-asserted-by":"publisher","award":["BFU2015-65103-R"],"award-info":[{"award-number":["BFU2015-65103-R"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci?n","doi-asserted-by":"publisher","award":["PID2021-124566OB-I00"],"award-info":[{"award-number":["PID2021-124566OB-I00"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci?n","doi-asserted-by":"publisher","award":["RTI2018-093935-B-I00"],"award-info":[{"award-number":["RTI2018-093935-B-I00"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,5,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Protein\u2013protein interactions (PPI) frequently involve \u03b1-helices and are challenging targets for small-molecule drugs. Here we report the design, synthesis and evaluation of new PPI inhibitors based on a bilaterally substituted p-terphenyl scaffold. The side groups of this scaffold are projected in a broad spatial angle and reproduced the interactions of the myosin A (MyoA) \u03b1-helix wrapped by the Myosin Tail Interacting Protein (MTIP) in Plasmodium parasites causing malaria. Fluorescence, calorimetry, and NMR spectroscopy analyses revealed that the terphenyl molecules recognized the MyoA binding site within the MTIP and were capable of displacing the \u03b1-helix from its protein receptor and triggering comparable conformational changes in MTIP. The MTIP affinity of the best inhibitor was strikingly close to that exhibited by the MyoA helix. These data indicate that a small-molecule terphenyl compound can efficiently mimic a four-times heavier polypeptide. These molecules may serve as probes for PPIs involving deeply buried \u03b1-helices.<\/jats:p>","DOI":"10.1021\/jacs.4c15031","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T23:14:12Z","timestamp":1746227652000},"page":"15917-15922","source":"Crossref","is-referenced-by-count":0,"title":["Bilaterally\nSubstituted Terphenyl Molecules Efficiently\nInhibit the Interaction between a Protein and a Fully Buried \u03b1-Helix\nin the Malaria Parasite Motor System"],"prefix":"10.1021","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5496-8784","authenticated-orcid":true,"given":"Saurabh","family":"Loharch","sequence":"first","affiliation":[{"name":"Universidad Cato\u0301lica de Valencia , , C\/Quevedo 2 , ,","place":["Valencia, Spain, 46001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Medina-Trillo","sequence":"additional","affiliation":[{"name":"Universidad Cato\u0301lica de Valencia , , C\/Quevedo 2 , ,","place":["Valencia, Spain, 46001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel M.","family":"Sedgwick","sequence":"additional","affiliation":[{"name":"Universidad de Valencia , Avda. V. A. Estelle\u0301s s\/n , ,","place":["Burjassot, Spain, 46100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7101-4037","authenticated-orcid":true,"given":"Pablo","family":"Barrio","sequence":"additional","affiliation":[{"name":"Universidad de Valencia , Avda. V. A. Estelle\u0301s s\/n , ,","place":["Burjassot, Spain, 46100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7575-9439","authenticated-orcid":true,"given":"Santos","family":"Fustero","sequence":"additional","affiliation":[{"name":"Universidad de Valencia , Avda. V. A. Estelle\u0301s s\/n , ,","place":["Burjassot, Spain, 46100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0627-6927","authenticated-orcid":true,"given":"Jose\u0301","family":"Gallego","sequence":"additional","affiliation":[{"name":"Universidad Cato\u0301lica de Valencia , , C\/Quevedo 2 , ,","place":["Valencia, Spain, 46001"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"issue":"1","key":"2026090713164384800_cit1","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.chembiol.2011.12.013","article-title":"Structural biology and drug discovery of difficult\ntargets: the limits of ligandability","volume":"19","author":"Surade","year":"2012","journal-title":"Chem Biol"},{"issue":"8","key":"2026090713164384800_cit2","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1038\/nrd.2016.29","article-title":"Small molecules, big\ntargets: drug discovery faces the protein-protein interaction challenge","volume":"15","author":"Scott","year":"2016","journal-title":"Nat Rev Drug Discov"},{"issue":"3","key":"2026090713164384800_cit3","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/nchem.1568","article-title":"Inhibition of \u03b1-helix-mediated\nprotein-protein interactions using designed molecules","volume":"5","author":"Azzarito","year":"2013","journal-title":"Nat Chem"},{"issue":"3","key":"2026090713164384800_cit4","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1016\/j.bmcl.2013.12.003","article-title":"\u03b1-Helix mimetics: outwards\nand upwards","volume":"24","author":"Jayatunga","year":"2014","journal-title":"Bioorg Med Chem Lett"},{"issue":"5","key":"2026090713164384800_cit5","doi-asserted-by":"publisher","first-page":"924","DOI":"10.3390\/pr10050924","article-title":"Helical Foldamers\nand Stapled Peptides as New Modalities in Drug Discovery: Modulators\nof Protein-Protein Interactions","volume":"10","author":"Tsuchiya","year":"2022","journal-title":"Processes"},{"issue":"36","key":"2026090713164384800_cit6","doi-asserted-by":"publisher","first-page":"14220","DOI":"10.1021\/ja206074j","article-title":"Assessing\nhelical protein interfaces\nfor inhibitor design","volume":"133","author":"Bullock","year":"2011","journal-title":"J Am Chem Soc"},{"issue":"21","key":"2026090713164384800_cit7","doi-asserted-by":"publisher","first-page":"2806","DOI":"10.1093\/bioinformatics\/btt483","article-title":"HippDB:\na database of readily targeted\nhelical protein-protein interactions","volume":"29","author":"Bergey","year":"2013","journal-title":"Bioinformatics"},{"issue":"50","key":"2026090713164384800_cit8","doi-asserted-by":"publisher","first-page":"13405","DOI":"10.1002\/anie.201306665","article-title":"Structure-Based Design\nof an RNA-Binding p-Terphenylene Scaffold that Inhibits HIV-1 Rev\nProtein Function","volume":"52","author":"Gonzalez-Bulnes","year":"2013","journal-title":"Angew Chem Int Ed"},{"key":"2026090713164384800_cit9","doi-asserted-by":"publisher","first-page":"7190","DOI":"10.1038\/s41598-020-64120-2","article-title":"Nucleic acid recognition and antiviral\nactivity of 1,4-substituted terphenyl compounds mimicking all faces\nof the HIV-1 Rev protein positively-charged alpha-helix","volume":"10","author":"Medina-Trillo","year":"2020","journal-title":"Sci. Rep."},{"key":"2026090713164384800_cit10","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1242\/jcs.00194","article-title":"Myosin A tail domain\ninteracting protein (MTIP) localizes to the inner membrane complex\nof Plasmodium sporozoites","volume":"116","author":"Bergman","year":"2003","journal-title":"J Cell Sci"},{"issue":"5","key":"2026090713164384800_cit11","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1016\/j.jmb.2005.11.027","article-title":"The MTIP-myosin\nA complex in blood stage malaria parasites","volume":"355","author":"Green","year":"2006","journal-title":"J Mol Biol"},{"issue":"11","key":"2026090713164384800_cit12","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1038\/nrmicro.2017.86","article-title":"Gliding motility\npowers invasion and egress in Apicomplexa","volume":"15","author":"Fre\u0301nal","year":"2017","journal-title":"Nat\nRev Microbiol"},{"issue":"1","key":"2026090713164384800_cit13","doi-asserted-by":"publisher","first-page":"3286","DOI":"10.1038\/s41467-019-11120-0","article-title":"Plasmodium myosin A drives parasite invasion by an\natypical force generating mechanism","volume":"10","author":"Robert-Paganin","year":"2019","journal-title":"Nat Commun"},{"issue":"1","key":"2026090713164384800_cit14","doi-asserted-by":"publisher","first-page":"3463","DOI":"10.1038\/s41467-023-38976-7","article-title":"Mechanism of small molecule\ninhibition of Plasmodium falciparum myosin A informs antimalarial\ndrug design","volume":"14","author":"Moussaoui","year":"2023","journal-title":"Nat Commun"},{"issue":"5","key":"2026090713164384800_cit15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3002110","article-title":"MyosinA is a druggable\ntarget in the widespread protozoan parasite Toxoplasma gondii","volume":"21","author":"Kelsen","year":"2023","journal-title":"PLoS Biol"},{"key":"2026090713164384800_cit16","doi-asserted-by":"publisher","DOI":"10.1101\/2022.09.09.507317","article-title":"A small-molecule myosin\ninhibitor\nas a targeted multi-stage antimalarial","author":"Trivedi","year":"2022","journal-title":"bioRxiv"},{"issue":"1","key":"2026090713164384800_cit17","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.jmb.2007.06.016","article-title":"The closed MTIP-myosin\nA-tail complex from the malaria\nparasite invasion machinery","volume":"372","author":"Bosch","year":"2007","journal-title":"J Mol Biol"},{"issue":"44","key":"2026090713164384800_cit18","doi-asserted-by":"publisher","first-page":"36968","DOI":"10.1074\/jbc.M112.379842","article-title":"Regulation\nof the Plasmodium motor complex: phosphorylation of myosin A tail-interacting\nprotein (MTIP) loosens its grip on MyoA","volume":"287","author":"Douse","year":"2012","journal-title":"J Biol\nChem"},{"issue":"13","key":"2026090713164384800_cit19","doi-asserted-by":"publisher","first-page":"4852","DOI":"10.1073\/pnas.0510907103","article-title":"Structure of the MTIP-MyoA\ncomplex, a key component of the malaria parasite invasion motor","volume":"103","author":"Bosch","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"38","key":"2026090713164384800_cit20","doi-asserted-by":"publisher","first-page":"4759","DOI":"10.1039\/b507375h","article-title":"Carbon\u2013carbon\nbonding made easy","author":"Suzuki","year":"2005","journal-title":"Chem. Commun."},{"issue":"3","key":"2026090713164384800_cit21","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1039\/b922093c","article-title":"Interaction\nand dynamics of the Plasmodium falciparum MTIP-MyoA complex, a key\ncomponent of the invasion motor in the malaria parasite","volume":"6","author":"Thomas","year":"2010","journal-title":"Mol Biosyst"},{"issue":"6","key":"2026090713164384800_cit22","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1021\/acschembio.0c00328","article-title":"Peptide Probes for\nPlasmodium falciparum MyoA Tail Interacting Protein (MTIP): Exploring\nthe Druggability of the Malaria Parasite Motor Complex","volume":"15","author":"Saunders","year":"2020","journal-title":"ACS Chem Biol"},{"issue":"22","key":"2026090713164384800_cit23","doi-asserted-by":"publisher","first-page":"5382","DOI":"10.1021\/ja0025548","article-title":"Toward\nproteomimetics: Terphenyl\nderivatives as structural and functional mimics of extended regions\nof an alpha-helix","volume":"123","author":"Orner","year":"2001","journal-title":"J. Am. Chem. Soc."},{"key":"2026090713164384800_cit24","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.60581","article-title":"Full-length Plasmodium\nfalciparum myosin A and essential light chain PfELC structures provide\nnew anti-malarial targets","volume":"9","author":"Moussaoui","year":"2020","journal-title":"Elife"},{"issue":"5","key":"2026090713164384800_cit25","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1021\/ci100039k","article-title":"Structure-based\ndesign of novel small-molecule inhibitors of Plasmodium falciparum","volume":"50","author":"Kortagere","year":"2010","journal-title":"J Chem Inf Model"},{"issue":"1","key":"2026090713164384800_cit26","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1002\/cmdc.201402357","article-title":"Targeting\na dynamic protein-protein interaction: fragment screening against\nthe malaria myosin A motor complex","volume":"10","author":"Douse","year":"2015","journal-title":"ChemMedChem"},{"issue":"10","key":"2026090713164384800_cit27","doi-asserted-by":"publisher","first-page":"2204","DOI":"10.1021\/cb500271c","article-title":"Crystal structures of stapled and\nhydrogen bond surrogate peptides targeting a fully buried protein-helix\ninteraction","volume":"9","author":"Douse","year":"2014","journal-title":"ACS Chem Biol"},{"issue":"1","key":"2026090713164384800_cit28","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1038\/s42003-020-01283-8","article-title":"Structural role of essential light chains in the apicomplexan\nglideosome","volume":"3","author":"Pazicky","year":"2020","journal-title":"Commun Biol"},{"issue":"20","key":"2026090713164384800_cit29","doi-asserted-by":"publisher","first-page":"3543","DOI":"10.1016\/j.tetlet.2007.03.108","article-title":"Facile synthesis\nof benzamides to mimic an \u03b1-helix","volume":"48","author":"Ahn","year":"2007","journal-title":"Tetrahedron\nLett."},{"issue":"15","key":"2026090713164384800_cit30","doi-asserted-by":"publisher","first-page":"5463","DOI":"10.1021\/ja0446404","article-title":"Terephthalamide\nderivatives as mimetics of helical peptides: disruption of the Bcl-x(L)\/Bak\ninteraction","volume":"127","author":"Yin","year":"2005","journal-title":"J Am Chem Soc"},{"key":"2026090713164384800_cit31","doi-asserted-by":"publisher","first-page":"7443","DOI":"10.1016\/j.tetlet.2006.08.048","article-title":"Intramolecular hydrogen\nbonding allows simple enaminones\nto structurally mimic the i, i + 4, and i + 7 residues of an \u03b1-he\u0301lix","volume":"47","author":"Rodriguez","year":"2006","journal-title":"Tetrahedron Lett."},{"issue":"45","key":"2026090713164384800_cit32","doi-asserted-by":"publisher","first-page":"8614","DOI":"10.1002\/anie.200701869","article-title":"Benzoylurea oligomers: synthetic\nfoldamers that mimic\nextended alpha helices","volume":"46","author":"Rodriguez","year":"2007","journal-title":"Angew Chem Int Ed Engl"}],"container-title":["Journal of the American Chemical Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jacs.4c15031","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/147\/19\/15917\/68419320\/jacs.4c15031.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/147\/19\/15917\/68419320\/jacs.4c15031.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T18:03:26Z","timestamp":1788804206000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jacsat\/article\/147\/19\/15917\/3737003\/Bilaterally-Substituted-Terphenyl-Molecules"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,2]]},"references-count":32,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2025,5,2]]},"published-print":{"date-parts":[[2025,5,14]]}},"URL":"https:\/\/doi.org\/10.1021\/jacs.4c15031","relation":{},"ISSN":["0002-7863","1520-5126"],"issn-type":[{"value":"0002-7863","type":"print"},{"value":"1520-5126","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,2]]}}}