Insertion of an Amphipathic Linker in a Tetrapodal Tryptophan Derivative Leads to a Novel and Highly Potent Entry Inhibitor of Enterovirus A71 Clinical Isolates
<b>AL-471</b>, the leading exponent of a class of potent HIV and enterovirus A71 (EV-A71) entry inhibitors discovered in our research group, contains four <span style="font-variant: small-caps;">l</span>-tryptophan (Trp) units bearing an aromatic isophthalic acid di...
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/4/3539 |
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| author | Olaia Martí-Marí Rana Abdelnabi Dominique Schols Johan Neyts María-José Camarasa Federico Gago Ana San-Félix |
| author_facet | Olaia Martí-Marí Rana Abdelnabi Dominique Schols Johan Neyts María-José Camarasa Federico Gago Ana San-Félix |
| author_sort | Olaia Martí-Marí |
| collection | DOAJ |
| description | <b>AL-471</b>, the leading exponent of a class of potent HIV and enterovirus A71 (EV-A71) entry inhibitors discovered in our research group, contains four <span style="font-variant: small-caps;">l</span>-tryptophan (Trp) units bearing an aromatic isophthalic acid directly attached to the C2 position of each indole ring. Starting from <b>AL-471</b>, we (i) replaced <span style="font-variant: small-caps;">l</span>-Trp with <span style="font-variant: small-caps;">d</span>-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 (<span style="font-variant: small-caps;">l</span>- or <span style="font-variant: small-caps;">d</span>-) 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, <b>23</b> (<b>AL-534</b>), 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 <b>AL-385</b> (12 <span style="font-variant: small-caps;">l</span>-Trp units) but remained unprecedented for the reduced-size prototype <b>AL-471</b>. Molecular modeling showed the feasibility of high-affinity binding of the novel <span style="font-variant: small-caps;">l</span>-Trp-decorated branches of <b>23</b> (<b>AL-534</b>) to an alternative site on the VP1 protein that harbors significant sequence variation among EV-71 strains. |
| first_indexed | 2024-03-11T08:42:34Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T08:42:34Z |
| publishDate | 2023-02-01 |
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| spelling | doaj.art-082313cde67a407c966bf63dc027464d2023-11-16T21:01:30ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01244353910.3390/ijms24043539Insertion of an Amphipathic Linker in a Tetrapodal Tryptophan Derivative Leads to a Novel and Highly Potent Entry Inhibitor of Enterovirus A71 Clinical IsolatesOlaia Martí-Marí0Rana Abdelnabi1Dominique Schols2Johan Neyts3María-José Camarasa4Federico Gago5Ana San-Félix6Instituto de Química Médica (IQM, CSIC), E-28006 Madrid, SpainLaboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, B-3000 Leuven, BelgiumLaboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, B-3000 Leuven, BelgiumLaboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, B-3000 Leuven, BelgiumInstituto de Química Médica (IQM, CSIC), E-28006 Madrid, SpainDepartamento de Ciencias Biomédicas y Unidad Asociada IQM-UAH, Universidad de Alcalá, E-28805 Alcalá de Henares, SpainInstituto de Química Médica (IQM, CSIC), E-28006 Madrid, Spain<b>AL-471</b>, the leading exponent of a class of potent HIV and enterovirus A71 (EV-A71) entry inhibitors discovered in our research group, contains four <span style="font-variant: small-caps;">l</span>-tryptophan (Trp) units bearing an aromatic isophthalic acid directly attached to the C2 position of each indole ring. Starting from <b>AL-471</b>, we (i) replaced <span style="font-variant: small-caps;">l</span>-Trp with <span style="font-variant: small-caps;">d</span>-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 (<span style="font-variant: small-caps;">l</span>- or <span style="font-variant: small-caps;">d</span>-) 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, <b>23</b> (<b>AL-534</b>), 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 <b>AL-385</b> (12 <span style="font-variant: small-caps;">l</span>-Trp units) but remained unprecedented for the reduced-size prototype <b>AL-471</b>. Molecular modeling showed the feasibility of high-affinity binding of the novel <span style="font-variant: small-caps;">l</span>-Trp-decorated branches of <b>23</b> (<b>AL-534</b>) to an alternative site on the VP1 protein that harbors significant sequence variation among EV-71 strains.https://www.mdpi.com/1422-0067/24/4/3539tryptophanSARantiviral agentsHIVEV71 |
| spellingShingle | Olaia Martí-Marí Rana Abdelnabi Dominique Schols Johan Neyts María-José Camarasa Federico Gago Ana San-Félix Insertion of an Amphipathic Linker in a Tetrapodal Tryptophan Derivative Leads to a Novel and Highly Potent Entry Inhibitor of Enterovirus A71 Clinical Isolates International Journal of Molecular Sciences tryptophan SAR antiviral agents HIV EV71 |
| 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 |
| title_full | Insertion of an Amphipathic Linker in a Tetrapodal Tryptophan Derivative Leads to a Novel and Highly Potent Entry Inhibitor of Enterovirus A71 Clinical Isolates |
| title_fullStr | Insertion of an Amphipathic Linker in a Tetrapodal Tryptophan Derivative Leads to a Novel and Highly Potent Entry Inhibitor of Enterovirus A71 Clinical Isolates |
| title_full_unstemmed | Insertion of an Amphipathic Linker in a Tetrapodal Tryptophan Derivative Leads to a Novel and Highly Potent Entry Inhibitor of Enterovirus A71 Clinical Isolates |
| title_short | Insertion of an Amphipathic Linker in a Tetrapodal Tryptophan Derivative Leads to a Novel and Highly Potent Entry Inhibitor of Enterovirus A71 Clinical Isolates |
| title_sort | insertion of an amphipathic linker in a tetrapodal tryptophan derivative leads to a novel and highly potent entry inhibitor of enterovirus a71 clinical isolates |
| topic | tryptophan SAR antiviral agents HIV EV71 |
| url | https://www.mdpi.com/1422-0067/24/4/3539 |
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