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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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