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Nowadays, HCMV infection is treated by inhibiting the viral DNA polymerase. However, DNA polymerase inhibitors have several drawbacks. An alternative strategy is to use compounds against the packaging machinery or terminase complex, which is essential for viral replication. Our discovery that raltegravir (1), a human immunodeficiency virus drug, inhibits the nuclease function of UL89, one of the protein subunits of the complex, prompted us to further develop terminase inhibitors. On the basis of the structure of 1, a library of diketoacid (\u03b1,\u03b3-DKA and \u03b2,\u03b4-DKA) derivatives were synthesized and tested for UL89-C nuclease activity. The mode of action of \u03b1,\u03b3-DKA derivatives on the UL89 active site was elucidated by using X-ray crystallography, molecular docking, and in vitro experiments. Our studies identified \u03b1,\u03b3-DKA derivative 14 able to inhibit UL89 in vitro in the low micromolar range, making 14 an optimal candidate for further development and virus-infected cell assay.<\/jats:p>","DOI":"10.1021\/acsomega.8b01472","type":"journal-article","created":{"date-parts":[[2018,8,1]],"date-time":"2018-08-01T11:21:58Z","timestamp":1533122518000},"page":"8497-8505","source":"Crossref","is-referenced-by-count":12,"title":["Structure-Driven Discovery of \u03b1,\u03b3-Diketoacid\nInhibitors Against UL89 Herpesvirus Terminase"],"prefix":"10.1021","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1309-3045","authenticated-orcid":true,"given":"Salvatore","family":"Bongarzone","sequence":"first","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona) , , Baldiri Reixac 10-12 , ,","place":["Barcelona, Spain, 08028"]},{"name":"Molecular Biology Institute of Barcelona (IBMB\u2500CSIC ), Barcelona Science Park, Baldiri Reixac 10-12 , ,","place":["Barcelona, Spain, 08028"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Nadal","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona) , , Baldiri Reixac 10-12 , ,","place":["Barcelona, Spain, 08028"]},{"name":"Molecular Biology Institute of Barcelona (IBMB\u2500CSIC ), Barcelona Science Park, Baldiri Reixac 10-12 , ,","place":["Barcelona, Spain, 08028"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuzanna","family":"Kaczmarska","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona) , , Baldiri Reixac 10-12 , ,","place":["Barcelona, Spain, 08028"]},{"name":"Molecular Biology Institute of Barcelona (IBMB\u2500CSIC ), Barcelona Science Park, Baldiri Reixac 10-12 , ,","place":["Barcelona, Spain, 08028"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Macho\u0301n","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona) , , Baldiri Reixac 10-12 , ,","place":["Barcelona, Spain, 08028"]},{"name":"Molecular Biology Institute of Barcelona (IBMB\u2500CSIC ), Barcelona Science Park, Baldiri Reixac 10-12 , ,","place":["Barcelona, Spain, 08028"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2025-9111","authenticated-orcid":true,"given":"Mercedes","family":"A\u0301lvarez","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona) , , Baldiri Reixac 10-12 , ,","place":["Barcelona, Spain, 08028"]},{"name":"CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine , Barcelona Science Park, ,","place":["Barcelona, Spain, 08028"]},{"name":"University of Barcelona , , ,","place":["Barcelona, Spain, 08028"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Albericio","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona) , , Baldiri Reixac 10-12 , ,","place":["Barcelona, Spain, 08028"]},{"name":"CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine , Barcelona Science Park, ,","place":["Barcelona, Spain, 08028"]},{"name":"University of Barcelona , , Marti\u0301 i Franque\u0300s 1 , ,","place":["Barcelona, Spain, 08028"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4471-8674","authenticated-orcid":true,"given":"Miquel","family":"Coll","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona) , , Baldiri Reixac 10-12 , ,","place":["Barcelona, Spain, 08028"]},{"name":"Molecular Biology Institute of Barcelona (IBMB\u2500CSIC ), Barcelona Science Park, Baldiri Reixac 10-12 , ,","place":["Barcelona, Spain, 08028"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2018,8,1]]},"reference":[{"key":"2026090414070295800_cit2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-540-77349-8_1","article-title":"Human Cytomegalovirus Genome","volume-title":"Human Cytomegalovirus","author":"Murphy","year":"2008"},{"key":"2026090414070295800_cit3","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1016\/j.antiviral.2006.05.002","article-title":"Antiviral\ndrugs for cytomegalovirus diseases","volume":"71","author":"Biron","year":"2006","journal-title":"Antiviral\nRes."},{"key":"2026090414070295800_cit4","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1517\/14656560802678138","article-title":"Antiviral\ntreatment of cytomegalovirus infection and\nresistant strains","volume":"10","author":"Schreiber","year":"2009","journal-title":"Expert Opin. Pharmacother."},{"key":"2026090414070295800_cit5","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1128\/aac.49.3.873-883.2005","article-title":"Human cytomegalovirus\nresistance to antiviral drugs","volume":"49","author":"Gilbert","year":"2005","journal-title":"Antimicrob. Agents\nChemother."},{"key":"2026090414070295800_cit6","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1128\/cmr.00009-10","article-title":"Antiviral drug resistance\nof human cytomegalovirus","volume":"23","author":"Lurain","year":"2010","journal-title":"Clin. Microbiol. Rev."},{"key":"2026090414070295800_cit7","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.jcv.2004.02.009","article-title":"Antiviral drugs in current clinical use","volume":"30","author":"De Clercq","year":"2004","journal-title":"J.\nClin. Virol."},{"key":"2026090414070295800_cit8","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/s1386-6532(01)00167-6","article-title":"Antiviral drugs: current state of the art","volume":"22","author":"De Clercq","year":"2001","journal-title":"J. Clin. Virol."},{"key":"2026090414070295800_cit9","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1002\/rmv.354","article-title":"Non-nucleoside\ninhibitors of herpesviruses","volume":"12","author":"Wathen","year":"2002","journal-title":"Rev. Med. Virol."},{"key":"2026090414070295800_cit10","doi-asserted-by":"publisher","first-page":"201","DOI":"10.2174\/187152609787847758","article-title":"Drug targets in cytomegalovirus infection","volume":"9","author":"Andrei","year":"2009","journal-title":"Infect. 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Virol."},{"key":"2026090414070295800_cit16","doi-asserted-by":"publisher","first-page":"1520","DOI":"10.1002\/prot.22669","article-title":"Insight into\nthe structure of the\npUL89 C-terminal domain of the human cytomegalovirus terminase complex","volume":"78","author":"Couvreux","year":"2010","journal-title":"Proteins"},{"key":"2026090414070295800_cit17","doi-asserted-by":"publisher","first-page":"1720","DOI":"10.1128\/jvi.01955-12","article-title":"The human cytomegalovirus UL51 protein\nis essential for viral genome cleavage-packaging and interacts with\nthe terminase subunits pUL56 and pUL89","volume":"87","author":"Borst","year":"2013","journal-title":"J. Virol."},{"key":"2026090414070295800_cit18","doi-asserted-by":"publisher","first-page":"16078","DOI":"10.1073\/pnas.1007144107","article-title":"Structure and inhibition\nof herpesvirus\nDNA packaging terminase nuclease domain","volume":"107","author":"Nadal","year":"2010","journal-title":"Proc.\nNatl. Acad. Sci. U.S.A."},{"key":"2026090414070295800_cit19","doi-asserted-by":"publisher","first-page":"10884","DOI":"10.1128\/jvi.05265-11","article-title":"The novel anticytomegalovirus compound\nAIC246 (Letermovir) inhibits human cytomegalovirus replication through\na specific antiviral mechanism that involves the viral terminase","volume":"85","author":"Goldner","year":"2011","journal-title":"J. Virol."},{"key":"2026090414070295800_cit20","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1128\/aac.01596-09","article-title":"In vitro and in vivo activities of the novel anticytomegalovirus\ncompound AIC246","volume":"54","author":"Lischka","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090414070295800_cit21","unstructured":"NCT02137772. ClinicalTrials.gov Bethesda (MD): National\nLibrary of\nMedicine (US). 2016 Dec. MK-8228 (Letermovir) Versus Placebo in the\nPrevention of Clinically-Significant Cytomegalovirus (CMV) Infection\nin Adult, CMV-Seropositive Allogeneic Hematopoietic Stem Cell Transplant\nRecipients (MK-8228\u2013001), (available from https:\/\/clinicaltrials.gov\/ct2\/show\/study\/NCT02137772, 2016)."},{"key":"2026090414070295800_cit22","doi-asserted-by":"publisher","first-page":"1695","DOI":"10.1093\/nar\/30.7.1695","article-title":"The terminase subunits\npUL56 and pUL89 of human cytomegalovirus\nare DNA-metabolizing proteins with toroidal structure","volume":"30","author":"Scheffczik","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"2026090414070295800_cit23","doi-asserted-by":"publisher","first-page":"8855","DOI":"10.1021\/bi0600796","article-title":"Identification of the Interaction Domain of the Small\nTerminase Subunit pUL89 with the Large Subunit pUL56 of Human Cytomegalovirus","volume":"45","author":"Thoma","year":"2006","journal-title":"Biochemistry"},{"key":"2026090414070295800_cit24","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1177\/135965350701200209","article-title":"New functional\ndomains of human cytomegalovirus pUL89 predicted by sequence analysis\nand three-dimensional modelling of the catalytic site DEXDc","volume":"12","author":"Champier","year":"2007","journal-title":"Antiviral Ther."},{"key":"2026090414070295800_cit25","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1177\/135965350801300504","article-title":"Putative functional\ndomains of human cytomegalovirus pUL56 involved in dimerization and\nbenzimidazole D-ribonucleoside activity","volume":"13","author":"Champier","year":"2008","journal-title":"Antiviral\nTher."},{"key":"2026090414070295800_cit26","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/s0166-3542(03)00108-6","article-title":"DNA encapsidation\nas a target for anti-herpesvirus\ndrug therapy","volume":"59","author":"Visalli","year":"2003","journal-title":"Antiviral Res."},{"key":"2026090414070295800_cit27","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1128\/JVI.72.1.717-725.1998","article-title":"Inhibition\nof human\ncytomegalovirus DNA maturation by a benzimidazole ribonucleoside is\nmediated through the UL89 gene product","volume":"72","author":"Underwood","year":"1998","journal-title":"J. Virol."},{"key":"2026090414070295800_cit28","doi-asserted-by":"crossref","first-page":"4721","DOI":"10.1128\/JVI.72.6.4721-4728.1998","article-title":"Resistance\nof human cytomegalovirus to benzimidazole\nribonucleosides maps to two open reading frames: UL89 and UL56","volume":"72","author":"Krosky","year":"1998","journal-title":"J. Virol."},{"key":"2026090414070295800_cit29","doi-asserted-by":"publisher","first-page":"14660","DOI":"10.1128\/jvi.79.23.14660-14667.2005","article-title":"Interaction\nof the putative human cytomegalovirus portal protein pUL104 with the\nlarge terminase subunit pUL56 and its inhibition by benzimidazole-D-ribonucleosides","volume":"79","author":"Dittmer","year":"2005","journal-title":"J. Virol."},{"key":"2026090414070295800_cit30","doi-asserted-by":"publisher","first-page":"1647","DOI":"10.1128\/aac.48.5.1647-1651.2004","article-title":"Mechanism of action\nof the ribopyranoside benzimidazole GW275175X against human cytomegalovirus","volume":"48","author":"Underwood","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090414070295800_cit31","doi-asserted-by":"publisher","first-page":"5753","DOI":"10.1021\/jm0400146","article-title":"Design, synthesis,\nand antiviral activity of certain 3-substituted 2,5,6-trichloroindole\nnucleosides","volume":"47","author":"Williams","year":"2004","journal-title":"J. Med. Chem."},{"key":"2026090414070295800_cit32","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1093\/jac\/48.6.757","article-title":"Novel non-nucleoside\ninhibitors of cytomegaloviruses (BAY 38-4766): in vitro and in vivo\nantiviral activity and mechanism of action","volume":"48","author":"Reefschlaeger","year":"2001","journal-title":"J. Antimicrob. Chemother."},{"key":"2026090414070295800_cit33","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1002\/j.1460-2075.1982.tb01276.x","article-title":"Distantly related\nsequences in the \u03b1- and \u03b2-subunits of ATP synthase, myosin,\nkinases and other ATP-requiring enzymes and a common nucleotide binding\nfold","volume":"1","author":"Walker","year":"1982","journal-title":"EMBO J."},{"key":"2026090414070295800_cit34","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.02152-16","article-title":"Inhibition of Human\nCytomegalovirus pUL89 Terminase Subunit Blocks Virus Replication and\nGenome Cleavage","volume":"91","author":"Wang","year":"2017","journal-title":"J. Virol."},{"key":"2026090414070295800_cit35","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.antiviral.2018.01.015","article-title":"Metal-chelating\n3-hydroxypyrimidine-2,4-diones inhibit human cytomegalovirus pUL89\nendonuclease activity and virus replication","volume":"152","author":"Wang","year":"2018","journal-title":"Antiviral Res."},{"key":"2026090414070295800_cit36","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1021\/acs.biochem.5b01254","article-title":"Characterization of the C-Terminal\nNuclease Domain\nof Herpes Simplex Virus pUL15 as a Target of Nucleotidyltransferase\nInhibitors","volume":"55","author":"Masaoka","year":"2016","journal-title":"Biochemistry"},{"key":"2026090414070295800_cit37","doi-asserted-by":"publisher","first-page":"11003","DOI":"10.1093\/nar\/gkv1018","article-title":"Two distinct\nmodes of metal ion binding\nin the nuclease active site of a viral DNA-packaging terminase: insight\ninto the two-metal-ion catalytic mechanism","volume":"43","author":"Zhao","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"2026090414070295800_cit38","doi-asserted-by":"publisher","first-page":"12596","DOI":"10.1074\/jbc.m110758200","article-title":"Structural\nDeterminants for HIV-1 Integrase Inhibition by \u03b2-Diketo Acids","volume":"277","author":"Marchand","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2026090414070295800_cit39","doi-asserted-by":"publisher","first-page":"5298","DOI":"10.1021\/jm049944f","article-title":"Design and Synthesis of Novel Indole\n\u03b2-Diketo Acid Derivatives as HIV-1 Integrase Inhibitors","volume":"47","author":"Sechi","year":"2004","journal-title":"J. Med. Chem."},{"key":"2026090414070295800_cit40","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1517\/13543776.12.5.709","article-title":"Patented small\nmolecule inhibitors of HIV-1 integrase: a 10-year saga","volume":"12","author":"Neamati","year":"2002","journal-title":"Expert Opin. Ther. Pat."},{"key":"2026090414070295800_cit41","doi-asserted-by":"publisher","first-page":"3292","DOI":"10.1128\/aac.46.10.3292-3297.2002","article-title":"Inhibition\nof human immunodeficiency virus type 1 integration by diketo derivatives","volume":"46","author":"Pluymers","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090414070295800_cit42","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1021\/jm0496077","article-title":"\u03b2-Diketo Acid\nPharmacophore Hypothesis. 1. Discovery\nof a Novel Class of HIV-1 Integrase Inhibitors","volume":"48","author":"Dayam","year":"2005","journal-title":"J. Med. Chem."},{"key":"2026090414070295800_cit43","doi-asserted-by":"publisher","first-page":"6661","DOI":"10.1073\/pnas.092056199","article-title":"Diketo acid inhibitor\nmechanism and\nHIV-1 integrase: implications for metal binding in the active site\nof phosphotransferase enzymes","volume":"99","author":"Grobler","year":"2002","journal-title":"Proc. Natl. Acad.\nSci. U.S.A."},{"key":"2026090414070295800_cit44","doi-asserted-by":"publisher","first-page":"5818","DOI":"10.1016\/j.bmcl.2006.08.075","article-title":"Exploration\nof the diketoacid integrase inhibitor chemotype leading to the discovery\nof the anilide-ketoacids chemotype","volume":"16","author":"Walker","year":"2006","journal-title":"Bioorg.\nMed. Chem. Lett."},{"key":"2026090414070295800_cit45","doi-asserted-by":"publisher","first-page":"4886","DOI":"10.1016\/j.bmcl.2007.06.042","article-title":"Benzyl amide-ketoacid\ninhibitors of HIV-integrase","volume":"17","author":"Walker","year":"2007","journal-title":"Bioorg. Med. Chem.\nLett."},{"key":"2026090414070295800_cit46","first-page":"460","article-title":"Metal chelators as\nantiviral agents","volume":"10","author":"Kirschberg","year":"2007","journal-title":"Curr. Opin. 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