1. Flexibility of small molecular CD4 mimics as HIV entry inhibitors.
- Author
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Kobayakawa T, Ohashi N, Hirota Y, Takahashi K, Yamada Y, Narumi T, Yoshimura K, Matsushita S, Harada S, and Tamamura H
- Subjects
- Binding Sites, Biomimetic Materials chemical synthesis, Biomimetic Materials chemistry, Biomimetic Materials toxicity, CD4 Antigens chemistry, Cell Line, Cell Survival drug effects, Glycine chemical synthesis, Glycine toxicity, HIV Envelope Protein gp120 chemistry, HIV Fusion Inhibitors chemical synthesis, HIV Fusion Inhibitors chemistry, HIV Fusion Inhibitors toxicity, HIV-1 chemistry, Humans, Indoles chemical synthesis, Indoles chemistry, Indoles toxicity, Molecular Docking Simulation, Pliability, Biomimetic Materials pharmacology, Glycine analogs & derivatives, Glycine pharmacology, HIV Fusion Inhibitors pharmacology, Indoles pharmacology
- 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., (Copyright © 2018. Published by Elsevier Ltd.)
- Published
- 2018
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