Development of 4'-C-ethynyl-2'-deoxy-2F-adenosine that is highly active against a multi-drug resistant HIV

• Project/Area Number: 14360062
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Bioproduction chemistry/Bioorganic chemistry
• Research Institution: Tohoku University
• Principal Investigator: OHRUI Hiroshi Tohoku University, Graduate School of Life Sciences, Professor, 大学院・生命科学研究科, 教授 (20100050)
• Co-Investigator(Kenkyū-buntansha): AKASAKA Kazuaki Tohoku University, Graduate School of Life Sciences, Associate Professor, 大学院・生命科学研究科, 助教授 (10201881)
• Project Period (FY): 2002 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥13,100,000 (Direct Cost: ¥13,100,000); Fiscal Year 2004: ¥2,800,000 (Direct Cost: ¥2,800,000); Fiscal Year 2003: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 2002: ¥7,100,000 (Direct Cost: ¥7,100,000)
• Keywords: AIDS chemotherapy / reverse-transcriptase-inhibitory nucleoside / resistant HIV / 2',3'-dideoxy nucleoside / physiologic 2'-deoxynucleoside / 4'-C-substituted-2'-deoxynucleoside / 4'-C-ethynyl-2'-deoxy-2-fluoroadenosine / nucleoside with unprecedentedly highly potent activity and no mouse toxicity / これまでの最高の抗HIV活性を有し且つマウス毒性ゼロのヌクレオシド / エイズの化学療法 / 抗HIV活性 / 4'-置換-2'-デオキシヌクレオシド / 多剤耐性HIV / カルボサイクリクヌクレオシド / 4'-置換ヌクレオシド / 3',4'-置換ヌクレオシド / アデノシンデアミナーゼ

Research Abstract

Recently CDC reported that they identified an AIDS patient to whom the combined chemotherapy was not effective at all. Thus, the problem to be urgently solved in AIDS chemotherapy is the development of the anti-HIV drug that prevents the emergence of drug-resistant HIV. This study aims the development of anti-HIV active nucleosides that prevent the emergence of resistant HIV-1 variants. Resistance to reverse-transcrptase(RT)-inhibitory 2',3'-dideoxynucleoside (ddN) indicates that HIVs can acquire the ability to discriminate between ddN and physiologic 2'-deoxynucleoside(dN) and/or eliminate the already incorporated ddN from the proviral DNA terminus. By taking the above mechanism into account and based on the following rationale (1) and (2), we have designed 4'-C-substituted-2'-deoxynucleoside(4'SdN) as the one that could be highly active against various HIVs and delay or does not allow the emergence of resistant HIVs. (1)4'SdN is very much like dN because it has all the functional groups of dN and therefore it could be very difficult for HIV to discriminate between them. (2)Quaternarization of the 4'-carbon makes the 3'-OH into a very unreactive neopentyl type secondary alcohol, therefore DNA biosynthesis would stop at 4'SdN and thus 4'SdN could be the chain-terminator of RT reaction. We have synthesized various kind of 4'SdNs. Some of them are highly active against a wide spectrum of HIVs but they were very toxic, too. Finally, we have reached to 4'-C-ethynyl-2'-deoxy-2-fluoroadenosine(2FA), which turned out to be unprecedentedly highly potent against all HIV-1 ; e.g.EC_<50>(IIIB)=0.2nM, (M184V)=3nM, (MDR)=0.15nM, S.I=110.000. No acute mouse toxicity up to 100kg/kg has been seen. 2FA is now under study for clinical use.

Research Products

• [Journal Article] Design, Efficient Synthesis, and Anti-HIV Activity of 4'-C-Cyano-and 4'-C-Ethynyl-2'-deoxy Purine Nucloesides (2004)
  • Author(s): S.Kohgo, K.Yamada, K.Kitano, Y.Iwai, S.Sakata, N.Ashida, H.Hayakawa, D.Nameki, E.Kodama, M.Matsuoka, H.Mitsuya, H.Ohrui
  • Journal Title: NUCLEOSIDES, NUCLEOTIDES&NUCLEIC ACIDS 23・4 Pages: 671-690
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Design, efficient Synthesis and Anti-HIV Activity of 4'-C-Cyano-and 4'-C-Ethynyl-2'-deoxy Purine Nucleosides (2004)
  • Author(s): S.Kohgo, K.Yamada, K.Kitano, Y.Iwai, S.Sakata, N.Ashida, H.Hayakawa, D.Nameki, E.Kodama, H.Mitsuya, H.Ohrui
  • Journal Title: NUCLEOSIDES, NUCLEOTIDES&NUCLEIC ACIDS vol23,No4 Pages: 671-690
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Design, Efficient Synthesis, and Anti-HIV Activity of 4'-C-Cyano- and 4'-C-Ethynyl-2'-deoxy Purine Nucloesides (2004)
  • Author(s): S.Kohgo, K.Yawada, K.Kitano, Y.Iwai, S.Sakata, N.Ashida, H.Hayakawa, D.Nameki, E.Kodama, M.Matsuoka, H.Mitsuya, H.Ohrui
  • Journal Title: NUCLEOSIDES, NUCLEOTIDES&NUCLEIC ACIDS 23・4 Pages: 671-690