Organotropic dendrons with high potency as HIV-1, HIV-2 and EV-A71 cell entry inhibitors

Dedicated to Prof. Dr. Jan Balzarini (KU Leuven, Belgium), in recognition of his exem- plary life-long dedication to virology and con- stant encouragementWe have recently described a novel family of compounds of reduced size and dual anti-HIV and anti-EV71 ac- tivity that encompasses tripodal and tetrapodal derivatives. The tripodal prototype, AL-470, has a nitro group at the focal point of the central scaffold and three attached tryptophan residues, each of which bearing an iso- phthaloyl moiety at the C2 position of the indole ring. A nitro to amino substitution has allowed us now to introduce a chemically addressable functionality to perform further structural modifications consisting of both direct and linker-mediated attachment of several aromatic groups, including the fluorescent dye Alexa Fluor 647 and the antibody-recruiting 2,4-dinitrophenyl motif. Some of the derivatives turned out to be more potent and selective than AL-470 against HIV-1, HIV-2 and EV-A71. The fluorescent probe demonstrated a specific tropism for intestines and lungs, two important niches for the human microbiome in health and diseaseThis work was supported by the Spanish MICINN (Projects PID2019- 104070RB-C21 and PID2019-104070RB-C22), and by the Spanish “Agencia Estatal Consejo Superior de Investigaciones Científicas” (CSIC, Projects CSIC-PIE-201980E100 and CSIC-PIE-201980E028). “The Cen- ters 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 (BEL- VIR) and the EU FP7 Industry-Academia Partnerships and Pathways Project AIROPICO. The Spanish MEC/MINECO is also acknowledged for grants to B.M-G and O.M-M. We thank Charlotte Vanderheydt, Sandra Claes, Caroline Collard, Daisy Ceusters and Kim Donckers, for helping with the evaluation and processing of the antiviral data. This work has been awarded with the Ramón Madroñero (XX call) prize within the “Prizes for Young Researchers of the Spanish Society of Medicinal Chemistry (SEQT).Peer reviewe