Flexibility of small molecular CD4 mimics as HIV entry inhibitors |
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Authors: | Takuya Kobayakawa Nami Ohashi Yuki Hirota Kohei Takahashi Yuko Yamada Tetsuo Narumi Kazuhisa Yoshimura Shuzo Matsushita Shigeyoshi Harada Hirokazu Tamamura |
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Institution: | 1. Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan;2. AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan;3. Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan |
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Abstract: | CD4 mimics such as YIR-821 and its derivatives are small molecules which inhibit the interaction between the Phe43 cavity of HIV-1 gp120 with host CD4, an interaction that is involved in the entry of HIV to cells. Known CD4 mimics generally possess three structural features, an aromatic ring, an oxalamide linker and a piperidine moiety. We have shown previously that introduction of a cyclohexyl group and a guanidine group into the piperidine moiety and a fluorine atom at the meta-position of the aromatic ring leads to a significant increase in the anti-HIV activity. In the current study, the effects of conformational flexibility were investigated by introduction of an indole-type group in the junction between the oxalamide linker and the aromatic moiety or by replacement of the oxalamide linker with a glycine linker. This led to the development of compounds with high anti-HIV activity, showing the importance of the junction region for the expression of high anti-HIV activity. The present data are expected to be useful in the future design of novel CD4 mimic molecules. |
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Keywords: | CD4 mimic Oxalamide linker Indole Entry inhibitor Anti-HIV |
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