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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 wide spectrum of human immunodeficiency viruses (HIV), including a variety of laboratory strains of HIV-1, HIV-2, and primary clinical HIV-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-1 replication with 50% effective concentrations ranging from 0.0003 to 0.01 µM in vitro with favorable cellular toxicity profiles (selectivity indices ranging 458 to 2,600). These 4'-E analogs also suppressed replication of various drug-resistant HIV-1 clones, including HIV-1M41L/T215Y, HIV-1K65R, HIV-1L74V, HIV-1M41L/T69S-S-G/T215Y, and HIV-1A62V/V75I/F77L/F116Y/Q151M. Moreover, these analogs inhibited the replication of multidrug-resistant clinical HIV-1 strains carrying a variety of drug resistance-related amino acid substitutions isolated from HIV-1-infected individuals for whom 10 or 11 different anti-HIV-1 agents had failed. The 4'-E analogs also blocked the replication of a non-nucleoside reverse transcriptase inhibitor-resistant clone, HIV-1Y181C, and showed an HIV-1 inhibition profile similar to that of zidovudine in time-of-drug-addition assays. The antiviral activity of 4'-E-thymidine and 4'-E-dC was blocked by the addition of thymidine and 2'-deoxycytidine, respectively, while that of 4'-E-dA was not affected by 2'-deoxyadenosine, similar to the antiviral activity reversion feature of 2',3'-dideoxynucleosides, strongly suggesting that 4'-E analogs belong to the family of nucleoside reverse transcriptase inhibitors. Further development of 4'-E analogs as potential therapeutics for infection with multidrug-resistant HIV-1 is warranted.

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

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.


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