Double Arylation of the Indole Side Chain of Tri- and Tetrapodal Tryptophan Derivatives Renders Highly Potent HIV-1 and EV-A71 Entry Inhibitors

Abstract

We have recently described a new generation of potent human immunodeficiency virus (HIV) and EV-A71 entry inhibitors. The prototypes contain three or four tryptophan (Trp) residues bearing an isophthalic acid moiety at the C2 position of each side-chain indole ring. This work is now extended by both shifting the position of the isophthalic acid to C7 and synthesizing doubly arylated C2/C7 derivatives. The most potent derivative (50% effective concentration (EC 50 ) HIV-1, 6 nM; EC 50 EV-A71, 40 nM), 33 ( AL-518 ), is a C2/C7 doubly arylated tetrapodal compound. Its superior anti-HIV potency with respect to the previous C2-arylated prototype is in consonance with its higher affinity for the viral gp120. 33 ( AL-518 ) showed comparable antiviral activities against X4 and R5 HIV-1 strains and seems to interact with the tip and base of the gp120 V3 loop. Taken together, these findings support the interest in 33 ( AL-518 ) as a useful new prototype for anti-HIV/EV71 drug development.

Insertion of an Amphipathic Linker in a Tetrapodal Tryptophan Derivative Leads to a Novel and Highly Potent Entry Inhibitor of Enterovirus A71 Clinical Isolates

“…Visual inspection of the models previously generated for AL-471 bound to the fivefold axis of the EV-A71 capsid protein VP1 [ 22 ] suggests that replacement of l -Trp units with d -Trp would generate similar binding modes for 6 ( Supporting Information ). With respect to HIV, the detailed models reporting the interaction of a membrane-embedded and heavily glycosylated HIV-1 Env trimer with the doubly arylated tetrapodal derivative AL-518 —previously described by our group [ 35 ]—revealed preferential binding to a location close to the V3 loop of gp120 that can be similarly targeted by the new 23 ( AL-534 ). Subtle differences in potency against HIV-1 and HIV-2 for 23 ( AL-534 ) are to be expected due to (i) well-known sequence and loop differences between HIV-1 and HIV-2, (ii) the multiple patterns of simultaneous CH···π stacking and hydrogen-bonding interactions that are possible between the distinct isophthalic acid-decorated Trp units and the oligomannose glycans attached to Asn residues at positions 134, 197, and 363 in HIV-1, (iii) modulation of electrostatic interactions with the side-chain guanidinium moieties of Arg151 (conserved in HIV-2) and Arg469 (Thr481 in HIV-2) [ 35 ], and (iv) the fact that antibodies do not usually cross-react between HIV-1 and HIV-2.…”

“…With respect to HIV, the detailed models reporting the interaction of a membrane-embedded and heavily glycosylated HIV-1 Env trimer with the doubly arylated tetrapodal derivative AL-518 —previously described by our group [ 35 ]—revealed preferential binding to a location close to the V3 loop of gp120 that can be similarly targeted by the new 23 ( AL-534 ). Subtle differences in potency against HIV-1 and HIV-2 for 23 ( AL-534 ) are to be expected due to (i) well-known sequence and loop differences between HIV-1 and HIV-2, (ii) the multiple patterns of simultaneous CH···π stacking and hydrogen-bonding interactions that are possible between the distinct isophthalic acid-decorated Trp units and the oligomannose glycans attached to Asn residues at positions 134, 197, and 363 in HIV-1, (iii) modulation of electrostatic interactions with the side-chain guanidinium moieties of Arg151 (conserved in HIV-2) and Arg469 (Thr481 in HIV-2) [ 35 ], and (iv) the fact that antibodies do not usually cross-react between HIV-1 and HIV-2. Studying this variation in depth is further complicated by the fact that Env proteins gp120 and gp41 subunits in the different HIV-1/HIV-2 subtypes or clades exist as populations of glycosylated variants (glycoforms) that are characterized by heterogeneous patches of oligomannose-type glycans at each N-linked glycosylation site.…”

C-2 Thiophenyl Tryptophan Trimers Inhibit Cellular Entry of SARS-CoV-2 through Interaction with the Viral Spike (S) Protein

“…Prior work from our group has shown multivalent functionalized tryptophan (Trp) derivatives to be potent inhibitors of different viruses, including human immunodeficiency virus (HIV), enterovirus 71 (EV-A71), and flavivirus infections, and to show low cytotoxicity. − Mechanistic studies demonstrated that these compounds interact with key elements of the viral surface (glycoprotein gp120 of HIV, 5-fold axis of the EV-A71 capsid and domain III of the viral envelope glycoprotein dengue 2 virus) preventing virus attachment to the host cell membranes. In previous studies, the existence of carboxylates at the Trps was shown to be critical for antiviral activity.…”