2. Academic Validation
  3. A minimally cytotoxic CD4 mimic as an HIV entry inhibitor

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-100039
    98.97%, CD4-mimic HIV Entry Inhibitor
    HIV