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

Abstract

Currently, there are only three FDA-approved drugs that inhibit human immunodeficiency virus (HIV) entry-fusion into host cells. 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 three or four 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 the fivefold 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.

Tryptophan Trimers and Tetramers Inhibit Dengue and Zika Virus Replication by Interfering with Viral Attachment Processes

“…The synthesis of trimers AL352, AL438, AL439, AL440, AL467, and AL455 ( Fig. 1) has been described recently (34). To complete the structureactivity relationship (SAR) studies, some novel compounds have been synthesized: trimers AL544, AL545, AL437, and AL484, tetramer AL531, and monomers AL441 and AL442 ( Fig.…”

Multivalent Tryptophan‐ and Tyrosine‐Containing [60]Fullerene Hexa‐Adducts as Dual HIV and Enterovirus A71 Entry Inhibitors

“…SAR studies led to the conclusion that a multivalent presentation of the Trp residues on these dendrimers is crucial for the observed activity against HIV and EV71 replication. [ 23 , 24 , 29 ] Therefore, in view of the above mentioned properties of the functionalized 3D fullerenes, we considered of interest the use of [60]fullerene as a multivalent scaffold to which twelve Trp residues could be attached (as is the case of AL‐385 ). Moreover, in order to determine the influence of the nature of the peripheral ligands on the activity, tyrosine (Tyr) residues were also attached to the [60]fullerene core.…”

Enterovirus Inhibition by Hinged Aromatic Compounds with Polynuclei

“…Liu et al [ 7 ] recorded many compounds isolated from biogenic sources with anti-EV71 activity over the period between 2005–2015. Recently reported anti-EV agents include aminopyridyl 1,2,5-thiadiazolidine 1,1-dioxides [ 8 ], 3-aryl-1,2,4-oxadiazoles [ 7 ], benzothiophenes [ 9 ], N 6 -benzyladenosine [ 10 ], 3-benzyl-1,3-benz-oxazine-2,4-diones [ 11 ], biaryl-substituted quinolones [ 12 ], diarylhydrazides [ 13 ], disaccharide heparan sulfates [ 5 ], epidithiodiketopiperazines [ 14 ], isopentenyladenosine [ 15 ], α-keto amides [ 16 , 17 ], nitrobenzonitriles [ 18 ], peptidomimetic aldehydes [ 19 ], quinoline–thiophene conjugates [ 20 ], sophoridine alkaloid [ 21 ], stilbenoids [ 22 ], multi-tryptophan derivatives [ 23 ], and others.…”