4'-Ethynyl Nucleoside Analogs: Potent Inhibitors of Multidrug-Resistant Human Immunodeficiency Virus Variants In Vitro

doi:10.1128/AAC.45.5.1539-1546.2001

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Antimicrobial Agents and Chemotherapy, May 2001, p. 1539-1546, Vol. 45, No. 5
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.5.1539-1546.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

4'-Ethynyl Nucleoside Analogs: Potent Inhibitors of Multidrug-Resistant Human Immunodeficiency Virus Variants In Vitro

Ei-Ichi Kodama,¹ Satoru Kohgo,² Kenji Kitano,³ Haruhiko Machida,³ Hiroyuki Gatanaga,⁴ Shiro Shigeta,⁵ Masao Matsuoka,¹^,⁶ Hiroshi Ohrui,² and Hiroaki Mitsuya⁴^,⁶^,^*

Laboratory of Virus Immunology, Institute for Virus Research, Kyoto University, Kyoto 606-8507,¹ Department of Applied Biological Chemistry, Faculty of Agriculture, Tohoku University, Sendai 981-8555,² Biochemicals Division, Yamasa Corporation, Chiba 288-0056,³ Department of Microbiology, Fukushima Medical University School of Medicine, Fukushima 960-1295,⁵ and Department of Immunopathophysiology and Internal Medicine II, Kumamoto University School of Medicine, Kumamoto 860-0811,⁶ Japan, and Experimental Retrovirology Section, Department of Developmental Therapeutics, Medicine Branch, National Cancer Institute, Bethesda, Maryland 20892⁴

Received 6 October 2000/Returned for modification 20 December 2000/Accepted 15 February 2001

A series of 4'-ethynyl (4'-E) nucleoside analogs were designed, synthesized, and identified as being active against a widespectrum of human immunodeficiency viruses (HIV), including avariety of laboratory strains of HIV-1, HIV-2, and primary clinicalHIV-1 isolates. Among such analogs examined, 4'-E-2'-deoxycytidine(4'-E-dC), 4'-E-2'-deoxyadenosine (4'-E-dA), 4'-E-2'-deoxyribofuranosyl-2,6-diaminopurine,and 4'-E-2'-deoxyguanosine were the most potent and blocked HIV-1replication with 50% effective concentrations ranging from 0.0003to 0.01 µM in vitro with favorable cellular toxicity profiles(selectivity indices ranging 458 to 2,600). These 4'-E analogsalso suppressed replication of various drug-resistant HIV-1 clones,including HIV-1_M41L/T215Y, HIV-1_K65R, HIV-1_L74V, HIV-1_{M41L/T69S-S-G/T215Y},and HIV-1_{A62V/V75I/F77L/F116Y/Q151M}. Moreover, these analogs inhibitedthe replication of multidrug-resistant clinical HIV-1 strainscarrying a variety of drug resistance-related amino acid substitutionsisolated from HIV-1-infected individuals for whom 10 or 11 differentanti-HIV-1 agents had failed. The 4'-E analogs also blocked thereplication of a non-nucleoside reverse transcriptase inhibitor-resistantclone, HIV-1_Y181C, and showed an HIV-1 inhibition profile similarto that of zidovudine in time-of-drug-addition assays. The antiviralactivity of 4'-E-thymidine and 4'-E-dC was blocked by the additionof thymidine and 2'-deoxycytidine, respectively, while that of4'-E-dA was not affected by 2'-deoxyadenosine, similar to theantiviral activity reversion feature of 2',3'-dideoxynucleosides,strongly suggesting that 4'-E analogs belong to the family ofnucleoside reverse transcriptase inhibitors. Further developmentof 4'-E analogs as potential therapeutics for infection with multidrug-resistantHIV-1 iswarranted.

^* Corresponding author. Mailing address: Medicine Branch, Building 10, Room 5A11, National Cancer Institute, 9000 RockvillePike, Bethesda, MD 20892. Phone: (301) 402-3631. Fax: (301) 402-0709.E-mail: hmitsuya{at}helix.nih.gov.

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