A minimally cytotoxic CD4 mimic as an HIV entry inhibitor

  • Bioorg Med Chem Lett. 2016 Jan 15;26(2):397-400. doi: 10.1016/j.bmcl.2015.11.103.
Takaaki Mizuguchi  1 ,  Shigeyoshi Harada  2 ,  Tomoyuki Miura  3 ,  Nami Ohashi  1 ,  Tetsuo Narumi  1 ,  Hiromi Mori  3 ,  Yu Irahara  1 ,  Yuko Yamada  4 ,  Wataru Nomura  1 ,  Shuzo Matsushita  5 ,  Kazuhisa Yoshimura  6 ,  Hirokazu Tamamura  7
Affiliations
  • 1. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan.
  • 2. AIDS Research Center, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan.
  • 3. Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
  • 4. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan; Pharmaceutical Department, Keio University Hospital, Shinjuku-ku, Tokyo 160-8582, Japan.
  • 5. Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan.
  • 6. AIDS Research Center, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan. Electronic address: [email protected].
  • 7. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan. Electronic address: [email protected].
PMID: 26706175 DOI: 10.1016/j.bmcl.2015.11.103
Abstract

Several CD4 mimics have been reported as HIV-1 entry inhibitors which can block the interaction between the viral envelope glycoprotein gp120 and the cell surface protein CD4. We previously found a lead compound 2 (YYA-021) with high anti-HIV activity and low cytotoxicity. Pharmacokinetic analysis however showed compound 2 to have wide tissue distribution and relatively high distribution volumes in rats and rhesus macaques. In the present study we searched for more hydrophilic CD4 mimics with a view to reducing tissue distribution. A new compound (5) with a 1,3-benzodioxolyl moiety was found to have relatively high anti-HIV activity and no significant cytotoxicity. Compound 5 is more hydrophilic than compound 2 and the pharmacokinetics of the intravenous administration of compound 5 in a rhesus macaque showed that compound 5 has lower tissue distribution than compound 2, suggesting that compound 5 possesses a better profile.

Keywords
CD4 mimic; Conformational change in gp120; HIV entry inhibitor; Pharmacokinetics.
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-100039
    YYA-021
    98.96%, CD4-mimic HIV Entry Inhibitor
    target: HIV
    Research Areas: Infection