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

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  • Additional Information
    • Source:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basel, Switzerland : MDPI, [2000-
    • Subject Terms:
      Enterovirus* ; Enterovirus A, Human* ; Enterovirus Infections* ; HIV Fusion Inhibitors*; Humans ; Tryptophan/metabolism ; Antiviral Agents/pharmacology
    • Abstract:
      AL-471 , the leading exponent of a class of potent HIV and enterovirus A71 (EV-A71) entry inhibitors discovered in our research group, contains four l-tryptophan (Trp) units bearing an aromatic isophthalic acid directly attached to the C2 position of each indole ring. 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.
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    • Grant Information:
      PID2019-104070RB-C21 and PID2019-104070RB-C22 [AEI/10.13039/501100011033 Spanish MICINN
    • Contributed Indexing:
      Keywords: EV71; HIV; SAR; antiviral agents; tryptophan
    • Accession Number:
      8DUH1N11BX (Tryptophan)
      121-91-5 (isophthalate)
      0 (Antiviral Agents)
      0 (HIV Fusion Inhibitors)
    • Publication Date:
      Date Created: 20230225 Date Completed: 20230228 Latest Revision: 20230228
    • Publication Date:
      20231215
    • Accession Number:
      PMC9959982
    • Accession Number:
      10.3390/ijms24043539
    • Accession Number:
      36834952