1. Exploratory studies on soluble small molecule CD4 mimics as HIV entry inhibitors.
- Author
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Tsuji K, Kobayakawa T, Konno K, Masuda A, Takahashi K, Ohashi N, Yoshimura K, Kuwata T, Matsushita S, Harada S, and Tamamura H
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, CD4 Antigens chemistry, Dose-Response Relationship, Drug, HIV Fusion Inhibitors chemical synthesis, HIV Fusion Inhibitors chemistry, Microbial Sensitivity Tests, Molecular Structure, Recombinant Proteins chemical synthesis, Recombinant Proteins chemistry, Recombinant Proteins pharmacology, Small Molecule Libraries chemical synthesis, Small Molecule Libraries chemistry, Solubility, Structure-Activity Relationship, Anti-HIV Agents pharmacology, HIV Envelope Protein gp120 antagonists & inhibitors, HIV Fusion Inhibitors pharmacology, HIV-1 drug effects, Small Molecule Libraries pharmacology
- Abstract
Several small molecule CD4 mimics, which inhibit the interaction of gp120 with CD4, have been developed. Original CD4 mimics such as NBD-556, which has an aromatic ring, an oxalamide linker and a piperidine moiety, possess significant anti-HIV activity but with their hydrophobic aromatic ring-containing structures are poorly soluble in water. We have developed derivatives with a halopyridinyl group in place of the phenyl group, such as KKN-134, and found them to have excellent aqueous solubility. Other leads that were examined are YIR-821, a compound with a cyclohexane group in a spiro attachment to a piperidine ring and a guanidino group on the piperidine nitrogen atom, and its PEGylated derivative, TKB-002. YIR-821 and TKB-002 retain potent anti-HIV activity. Here, new CD4 mimics, in which the phenyl group was replaced by a halopyridinyl group with the halogen atoms in different positions, their derivatives without a cyclohexane group on the piperidine ring and their hybrid molecules with PEG units were designed and synthesized. Some of these compounds show significantly higher aqueous solubility with maintenance of certain levels of anti-HIV activity. The present data should be useful in the future design of CD4 mimic molecules., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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