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

Unprecedented 3D hexa-adducts of [60]fullerene peripherally decorated with twelve tryptophan (Trp) or tyrosine (Tyr) residues have been synthesized. Studies on the antiviral activity of these novel compounds against HIV and EV71 reveal that they are much more potent against HIV and equally active against EV71 than the previously described dendrimer prototypes AL-385 and AL-463, which possess the same number of Trp/Tyr residues on the periphery but attached to a smaller and more flexible pentaerythritol core. These results demonstrate the relevance of the globular 3D presentation of the peripheral groups (Trp/Tyr) as well as the length of the spacer connecting them to the central core to interact with the viral envelopes, particularly in the case of HIV, and support the hypothesis that [60]fullerene can be an alternative and attractive biocompatible carbon-based scaffold for this type of highly symmetrical dendrimers. In addition, the functionalized fullerenes here described, which display twelve peripheral negatively charged indole moieties on their globular surface, define a new and versatile class of compounds with a promising potential in biomedical applications.
This work has been supported by the Spanish MINECO/FEDER (Projects CTQ2017-84327-P and CTQ2017-83531-R), the Spanish MICINN (Projects PID2019-104070RB-C21 and PID2019- 104070RB-C22), the Spanish Agencia Estatal Consejo Superior de Investigaciones Científicas (CSIC, Projects CSIC-PIE- 201980E100 and CSIC-PIE-201980E028), “The Centers of Excellence” of the KU Leuven (EF-05/15 and PF-10/18), EU FP7 (FP7/ 2007–2013) Project EUVIRNA (Grant 408 Agreement 264286), EU FP7 SILVER (Contract HEALTH-F3-2010-260644), a grant from the Belgian Interuniversity Attraction Poles (IAP) Phase VII-P7/45 (BELVIR) and the EU FP7 Industry-Academia Partnerships and Pathways Project AIROPICO. The Spanish MEC/MINECO is also acknowledged for a grant to O. M.-M. We also thank Charlotte Vanderheydt, Caroline Collard, Kim Donckers, Sandra Claes and Evelyne Van Kerckhove for help with the processing of the antiviral data.