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Starting from AL-471, we (i) replaced l-Trp with d-Trp, (ii) inserted a flexible linker between C2 and the isophthalic acid, and (iii) substituted a nonaromatic carboxylic acid for the terminal isophthalic acid. Truncated analogues lacking the Trp motif were also synthesized. Our findings indicate that the antiviral activity seems to be largely independent of the stereochemistry (l- or d-) of the Trp fragment and also that both the Trp unit and the distal isophthalic moiety are essential for antiviral activity. The most potent derivative, 23 (AL-534), with the C2 shortest alkyl urea linkage (three methylenes), showed subnanomolar potency against different EV-71 clinical isolates. This finding was only observed before with the early dendrimer prototype AL-385 (12 l-Trp units) but remained unprecedented for the reduced-size prototype AL-471. Molecular modeling showed the feasibility of high-affinity binding of the novel l-Trp-decorated branches of 23 (AL-534) to an alternative site on the VP1 protein that harbors significant sequence variation among EV-71 strains.<\/jats:p>","DOI":"10.3390\/ijms24043539","type":"journal-article","created":{"date-parts":[[2023,2,10]],"date-time":"2023-02-10T02:56:13Z","timestamp":1675997773000},"page":"3539","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Insertion of an Amphipathic Linker in a Tetrapodal Tryptophan Derivative Leads to a Novel and Highly Potent Entry Inhibitor of Enterovirus A71 Clinical Isolates"],"prefix":"10.3390","volume":"24","author":[{"given":"Olaia","family":"Mart\u00ed-Mar\u00ed","sequence":"first","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica (IQM, CSIC), E-28006 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9771-7312","authenticated-orcid":false,"given":"Rana","family":"Abdelnabi","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, B-3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3256-5850","authenticated-orcid":false,"given":"Dominique","family":"Schols","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, B-3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0033-7514","authenticated-orcid":false,"given":"Johan","family":"Neyts","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, B-3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4978-6468","authenticated-orcid":false,"given":"Mar\u00eda-Jos\u00e9","family":"Camarasa","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica (IQM, CSIC), E-28006 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3071-4878","authenticated-orcid":false,"given":"Federico","family":"Gago","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas y Unidad Asociada IQM-UAH, Universidad de Alcal\u00e1, E-28805 Alcal\u00e1 de Henares, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4271-7598","authenticated-orcid":false,"given":"Ana","family":"San-F\u00e9lix","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica (IQM, CSIC), E-28006 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,10]]},"reference":[{"key":"ref_1","unstructured":"United Nations Programme on HIV\/Aids (2021, November 29). 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