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Antimicrobial Agents and Chemotherapy, August 2005, p. 3355-3360, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3355-3360.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Anti-Human Immunodeficiency Virus Type 1 Activity and Resistance Profile of 2',3'-Didehydro-3'-Deoxy-4'-Ethynylthymidine In Vitro

Takao Nitanda,1 Xin Wang,1 Hiroki Kumamoto,2 Kazuhiro Haraguchi,2 Hiromichi Tanaka,2 Yung-Chi Cheng,3 and Masanori Baba1*

Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544,1 School of Pharmaceutical Sciences, Showa University, Tokyo 142-8555, Japan,2 Department of Pharmacology, School of Medicine, Yale University, New Haven, Connecticut 065203

Received 19 February 2005/ Returned for modification 28 April 2005/ Accepted 26 May 2005

2',3'-Didehydro-3'-deoxy-4'-ethynylthymidine (4'-Ed4T) has been identified as a novel nucleoside analog with potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity and weak cytotoxicity in cell cultures. 4'-Ed4T proved to be 5- to 10-fold more active than its structurally related compound, stavudine (d4T). However, the drug resistance profile of 4'-Ed4T was different from those of d4T and other existing HIV-1 nucleoside reverse transcriptase inhibitors (NRTIs). Approximately 6- to 11-fold decreases in susceptibility to 4'-Ed4T were observed for HIV-1 carrying NRTI-associated mutations (D67N, K70R, T215F, and K219Q) or the lamivudine (3TC)-resistant mutation M184V. In contrast, the susceptibility of the virus carrying the K65R mutation or the multidrug-resistant mutation with the Q151M complex (A62V, V75I, F77L, F116Y, and Q151M) was not altered. Furthermore, the activity of 4'-Ed4T appeared to be enhanced in the presence of K103N, a major nonnucleoside reverse transcriptase inhibitor-resistant mutation. Although 4'-Ed4T was 4.5- to 17.5-fold less active against multidrug-resistant clinical isolates than against a reference strain isolated from a treatment-naïve patient, it was still inhibitory to these isolates at low concentrations. Analysis of 4'-Ed4T-resistant HIV-1 obtained through in vitro selection revealed that the virus was also resistant to 3TC and had two amino acid mutations (P119S and T165A) in addition to the M184V mutation. Since 4'-Ed4T has increased anti-HIV-1 activity, decreased cytotoxicity, and a different resistance profile, it should be considered for further development as a new member of NRTIs.

* Corresponding author. Mailing address: Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan. Phone: 81 (99) 275-5930. Fax: 81 (99) 275-5932. E-mail: baba{at}m.kufm.kagoshima-u.ac.jp.

Antimicrobial Agents and Chemotherapy, August 2005, p. 3355-3360, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3355-3360.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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