Scaffold Simplification Strategy Leads to a Novel Generation of Dual Human Immunodeficiency Virus and Enterovirus-A71 Entry Inhibitors [component]

unpublished
The entry-fusion process is one of the most promising targets to develop new classes of effective anti-HIV drugs but currently there are only two inhibitors of this class approved by the FDA and none of them binds to the envelope glycoprotein gp120. The situation is even worse for enterovirus EV71 infection for which no antiviral therapies are available. We describe here the discovery of potent entry dual inhibitors of HIV and EV71. These compounds contain in their structure 3 or 4 tryptophan
more » ... 3 or 4 tryptophan (Trp) residues linked to a central scaffold. Critical for anti-HIV/EV71 activity is the presence of extra phenyl rings, bearing one or two carboxylates, at the C2 position of the indole ring of each Trp residue. The most potent derivatives, 22 and 30, inhibit early steps of the replicative cycles of HIV-1 and EV-A71 by interacting with their respective viral surfaces (glycoprotein gp120 of HIV and 5-fold axis of the EV-A71 capsid). The high potency, low toxicity, facile chemical synthesis and great opportunities for chemical optimization make them useful prototypes for future medicinal chemistry studies.
doi:10.1021/acs.jmedchem.9b01737.s002 fatcat:vrymghnyhzf3lh5ngtn6fxuxja