Hybrids of Small-Molecule CD4 Mimics with Polyethylene Glycol Units as HIV Entry Inhibitors

CD4 mimics are small molecules that
inhibit the interaction of
gp120 with CD4. We have developed several CD4 mimics. Herein, hybrid
molecules consisting of CD4 mimics with a long alkyl chain or a PEG
unit attached through a self-cleavable linker were synthesized. In
anti-HIV activity, modification with a PEG unit appeared to be more
suitable than modification with a long alkyl chain. Thus, hybrid molecules
of CD4 mimics, with PEG units attached through an uncleavable linker,
were developed and showed high anti-HIV activity and low cytotoxicity.
In investigation of pharmacokinetics in a rhesus macaque, a hybrid
compound had a more effective PK profile than that of the parent compound,
and intramuscular injection was a more useful administration route
to maintain the high blood concentration of the CD4 mimic than intravenous
injection. The presented hybrid molecules of CD4 mimics with a PEG
unit would be practically useful when combined with a neutralizing
antibody.