{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T16:52:18Z","timestamp":1761929538755},"reference-count":34,"publisher":"American Society for Microbiology","issue":"11","license":[{"start":{"date-parts":[[2011,11,1]],"date-time":"2011-11-01T00:00:00Z","timestamp":1320105600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2011,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>(<jats:italic>S<\/jats:italic>)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC [cidofovir]) and (<jats:italic>S<\/jats:italic>)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (HPMPA) are potent inhibitors of a variety of DNA viruses. These drugs possess a 3\u2032-hydroxyl equivalent which could support chain extension from an incorporated drug molecule. HPMPC and HPMPA were initially reported to lack activity against human immunodeficiency virus type 1 (HIV-1); more recent results have shown that the octadecyloxyethyl (ODE) and hexadecyloxypropyl (HDP) esters of HPMPA are potent inhibitors of the virus. We have synthesized the ODE esters of a series of (<jats:italic>S<\/jats:italic>)-[3-hydroxy-2-(phosphonomethoxy)propyl] (HPMP) nucleosides, including HPMPC, HPMP-guanine (HPMPG), HPMP-thymine (HPMPT), and HPMP-diaminopurine (HPMPDAP), as well as the ODE ester of the obligate chain terminator (<jats:italic>S<\/jats:italic>)-9-[3-methoxy-2-(phosphonomethoxy)-propyl]adenine (MPMPA). All compounds except ODE-HPMPT were inhibitors of HIV-1 replication at low nanomolar concentrations. These compounds were also inhibitors of the replication of HIV-1 variants that are resistant to various nucleoside reverse transcriptase (RT) inhibitors at concentrations several times lower than would be expected to be achieved<jats:italic>in vivo<\/jats:italic>. To investigate the mechanism of the antiviral activity, the active metabolites of HPMPC and HPMPA were studied for their effects on reactions catalyzed by HIV-1 RT. Incorporation of HPMPC and HPMPA into a DNA primer strand resulted in multiple inhibitory effects exerted on the enzyme and showed that neither compound acts as an absolute chain terminator. Further, inhibition of HIV-1 RT also occurred when these drugs were located in the template strand. These results indicate that HPMPC and HPMPA inhibit HIV-1 by a complex mechanism and suggest that this class of drugs has a broader spectrum of activity than previously shown.<\/jats:p>","DOI":"10.1128\/aac.05161-11","type":"journal-article","created":{"date-parts":[[2011,9,7]],"date-time":"2011-09-07T03:46:33Z","timestamp":1315367193000},"page":"5063-5072","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":10,"title":["Inhibition of HIV-1 by Octadecyloxyethyl Esters of (<i>S<\/i>)-[3-Hydroxy-2-(Phosphonomethoxy)Propyl] Nucleosides and Evaluation of Their Mechanism of Action"],"prefix":"10.1128","volume":"55","author":[{"given":"Wendy C.","family":"Magee","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, 6020 K, Katz Group Centre, University of Alberta, Edmonton, AB T6G 2E1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadejda","family":"Valiaeva","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Diego, 9500 Gilman Drive, Mail Code 0676, La Jolla, California 92093"},{"name":"Veterans Medical Research Foundation, 3350 La Jolla Village Drive, San Diego, California 92161"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James R.","family":"Beadle","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Diego, 9500 Gilman Drive, Mail Code 0676, La Jolla, California 92093"},{"name":"Veterans Medical Research Foundation, 3350 La Jolla Village Drive, San Diego, California 92161"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas D.","family":"Richman","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Diego, 9500 Gilman Drive, Mail Code 0676, La Jolla, California 92093"},{"name":"Veterans Medical Research Foundation, 3350 La Jolla Village Drive, San Diego, California 92161"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karl Y.","family":"Hostetler","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Diego, 9500 Gilman Drive, Mail Code 0676, La Jolla, California 92093"},{"name":"Veterans Medical Research Foundation, 3350 La Jolla Village Drive, San Diego, California 92161"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David H.","family":"Evans","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, 6020 K, Katz Group Centre, University of Alberta, Edmonton, AB T6G 2E1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.63.3.678"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00605-06"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-3542(02)00196-1"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.37.2.332"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.46.8.2381-2386.2002"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm050473m"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.40.5.1270"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(04)16500-8"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1877"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/323464a0"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-3542(87)80004-9"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M707834200"},{"key":"e_1_3_2_14_2","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1177\/135965350801300113","article-title":"Gln151 of HIV-1 reverse transcriptase acts as a steric gate towards clinically relevant acyclic phosphonate nucleotide analogues","volume":"13","author":"Frangeul A.","year":"2008","unstructured":"FrangeulA.. 2008. Gln151 of HIV-1 reverse transcriptase acts as a steric gate towards clinically relevant acyclic phosphonate nucleotide analogues. Antivir. Ther. 13:115\u2013124.","journal-title":"Antivir. Ther."},{"key":"e_1_3_2_15_2","unstructured":"GilbertD. N. MoelleringR. C.Jr. EliopoulosG. M. ChambersH. F. SaagM. S.. 2010. The Sanford guide to antimicrobial therapy 40th ed. Antimicrobial Therapy Inc. Sperryville VA."},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.6.1621-1628.2001"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2009.01.005"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01223-05"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2004.10.049"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.37.5.1095"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja109823e"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00380-06"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.3390\/v2122740"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01172-07"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.8.3153-3162.2005"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008886"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00460-07"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.32.7.1025"},{"key":"e_1_3_2_29_2","volume-title":"Molecular cloning: a laboratory manual","author":"Sambrook J.","year":"2001","unstructured":"SambrookJ. RussellD. W.. 2001. Molecular cloning: a laboratory manual, 3rd ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.","edition":"3"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-3542(97)01035-8"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M806797200"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2009.09.012"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2011.06.009"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo00836a045"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.3.594"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.05161-11","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.05161-11","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T07:02:17Z","timestamp":1686294137000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.05161-11"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,11]]},"references-count":34,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2011,11]]}},"alternative-id":["10.1128\/AAC.05161-11"],"URL":"https:\/\/doi.org\/10.1128\/aac.05161-11","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,11]]},"assertion":[{"value":"2011-06-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2011-08-24","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2011-10-14","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}