TY - JOUR
T1 - Creation of low toxic reverse-transcriptase inhibitory nucleosides that prevent the emergence of drug-resistant HIV variants
AU - Ohrui, Hiroshi
AU - Hayakawa, Hiroyuki
AU - Kohgo, Satoru
AU - Matsuoka, Masao
AU - Kodama, Eiichi
AU - Mitsuya, Hiroaki
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2006/7
Y1 - 2006/7
N2 - Although the Highly Active Anti-Retroviral Therapy (HAART) has dramatically improved the quality of life and the prognosis of patients infected with HIV, development of more active and less toxic drugs that prevent the emergence of drug-resistant HIV variants is strongly required, due to the emergence of new drug-resistant HIV variants, need of taking a large quantity of drugs, and side effects of the drugs. The principal author has proposed a concept to prevent the emergence of the HIV variants resistant to reverse-transcriptase (RT) inhibitory nucleosides. Based on the concept, 4′ -C-substituted-2′-deoxynucleoside (4′Sd-N)* 1 was designed as the anti-HIV nucleoside that could prevent the emergence of resistant HIV variants. Various kinds of 4′Sd-N were synthesized and evaluated for biological activity. 2′-Deoxy-4′-C-ethynyl-2-fluoroadenosine (4′Ed-2FA) which is stable to adenosine deaminase turned out to be highly active against all HIV-1 including multi-drug resistant variants and very lowly toxic, and so far no HIV-1 variants resistant to it emerged. These results suggest that once-daily-dosing schedule of 4′Ed-2FA is possible presumably with few side effects and warrant that 4′Ed-2FA be further developed as a potential therapeutic for HIV-1 infection.
AB - Although the Highly Active Anti-Retroviral Therapy (HAART) has dramatically improved the quality of life and the prognosis of patients infected with HIV, development of more active and less toxic drugs that prevent the emergence of drug-resistant HIV variants is strongly required, due to the emergence of new drug-resistant HIV variants, need of taking a large quantity of drugs, and side effects of the drugs. The principal author has proposed a concept to prevent the emergence of the HIV variants resistant to reverse-transcriptase (RT) inhibitory nucleosides. Based on the concept, 4′ -C-substituted-2′-deoxynucleoside (4′Sd-N)* 1 was designed as the anti-HIV nucleoside that could prevent the emergence of resistant HIV variants. Various kinds of 4′Sd-N were synthesized and evaluated for biological activity. 2′-Deoxy-4′-C-ethynyl-2-fluoroadenosine (4′Ed-2FA) which is stable to adenosine deaminase turned out to be highly active against all HIV-1 including multi-drug resistant variants and very lowly toxic, and so far no HIV-1 variants resistant to it emerged. These results suggest that once-daily-dosing schedule of 4′Ed-2FA is possible presumably with few side effects and warrant that 4′Ed-2FA be further developed as a potential therapeutic for HIV-1 infection.
KW - AIDS
KW - Anti-HIV-1 drug free from emergence of resistant HIV-1 variant
KW - Drug-resistant HIV
KW - HIV
KW - Highly active anti-retroviral therapy (HAART)
KW - Prevention of the emergence of drug-resistant HIV
KW - RT-inhibitory nucleoside
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U2 - 10.5059/yukigoseikyokaishi.64.716
DO - 10.5059/yukigoseikyokaishi.64.716
M3 - Article
AN - SCOPUS:33748579925
VL - 64
SP - 716
EP - 723
JO - Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry
JF - Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry
SN - 0037-9980
IS - 7
ER -