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

• Published in: European journal of medicinal chemistry Vol. 237; p. 114414
• Main Authors: Martí-Marí, Olaia, Martínez-Gualda, Belén, Fernández-Barahona, Irene, Mills, Alberto, Abdelnabi, Rana, Noppen, Sam, Neyts, Johan, Schols, Dominique, Camarasa, María-José, Herranz, Fernando, Gago, Federico, San-Félix, Ana
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.07.2022; Elsevier
• Subjects: Biodistribution; Chemistry, Medicinal; Dendrimers - chemistry; Enterovirus A, Human; Enterovirus Infections; EV71; Fluorescence imaging; HIV; HIV Fusion Inhibitors - pharmacology; HIV-1; HIV-2; Humans; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; Viral entry inhibitors; Virus Internalization; Fluorescence imaging; EV71; HIV; Biodistribution; Viral entry inhibitors; LUNG; TRYPTOPHAN DENDRIMERS; GP120; HUMAN-IMMUNODEFICIENCY-VIRUS; CHILDREN; REPLICATION; ENVELOPE GLYCOPROTEINS; ENTEROVIRUS-71 INFECTION; LEADS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114414

We have recently described a novel family of compounds of reduced size and dual anti-HIV and anti-EV71 activity 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 isophthaloyl 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 disease. A fluorescent dendron accumulates in intestines and lungs!. [Display omitted] •The focal point of Trp dendrons was functionalized without loss of antiviral potency.•AL-525 is more potent and selective (EV-A71) than the early prototype AL-470.•AL-558 is more potent and selective (HIV-1/HIV-2) than the early prototype AL-470.•A fluorescent probe demonstrated in mice a remarkable tropism for intestines/lungs.