1. Halting the Spread of Herpes Simplex Virus-1: The Discovery of an Effective Dual αvβ6/αvβ8 Integrin Ligand
- Author
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Stefano Tomassi, Francesco Saverio Di Leva, Giovanna Musco, Salvatore Di Maro, Horst Kessler, Michael Weinmüller, Tatiana Gianni, Barbara Romano, Jussara Amato, Giacomo Quilici, Ettore Novellino, Angelo A. Izzo, Andrea Vannini, Florian Reichart, Vincenzo Maria D'Amore, Luciana Marinelli, Tomassi, S., D'Amore, V. M., Di Leva, F. S., Vannini, A., Quilici, G., Weinmuller, M., Reichart, F., Amato, J., Romano, B., Izzo, A. A., Di Maro, S., Novellino, E., Musco, G., Gianni, T., Kessler, H., Marinelli, L., Tomassi S., D'Amore V.M., Di Leva F.S., Vannini A., Quilici G., Weinmuller M., Reichart F., Amato J., Romano B., Izzo A.A., Di Maro S., Novellino E., Musco G., Gianni T., Kessler H., and Marinelli L.
- Subjects
Integrins ,Small interfering RNA ,Molecular model ,Integrin ,Peptide ,Herpesvirus 1, Human ,Integrin ligand ,Ligands ,medicine.disease_cause ,Peptides, Cyclic ,01 natural sciences ,Article ,03 medical and health sciences ,HEK293 Cell ,Antigens, Neoplasm ,Drug Discovery ,medicine ,Humans ,030304 developmental biology ,chemistry.chemical_classification ,Infectivity ,0303 health sciences ,Binding Sites ,biology ,Binding Site ,Virus Internalization ,Combined approach ,ddc ,0104 chemical sciences ,Cell biology ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,HEK293 Cells ,Herpes simplex virus ,chemistry ,biology.protein ,Oligopeptide ,Molecular Medicine ,Oligopeptides ,Human ,Protein Binding - Abstract
Over recent years, αvβ6 and αvβ8 Arg-Gly-Asp (RGD) integrins have risen to prominence as interchangeable co-receptors for the cellular entry of herpes simplex virus-1 (HSV-1). In fact, the employment of subtype-specific integrin-neutralizing antibodies or gene-silencing siRNAs has emerged as a valuable strategy for impairing HSV infectivity. Here, we shift the focus to a more affordable pharmaceutical approach based on small RGD-containing cyclic pentapeptides. Starting from our recently developed αvβ6-preferential peptide [RGD-Chg-E]-CONH2 (1), a small library of N-methylated derivatives (2–6) was indeed synthesized in the attempt to increase its affinity toward αvβ8. Among the novel compounds, [RGD-Chg-(NMe)E]-CONH2 (6) turned out to be a potent αvβ6/αvβ8 binder and a promising inhibitor of HSV entry through an integrin-dependent mechanism. Furthermore, the renewed selectivity profile of 6 was fully rationalized by a NMR/molecular modeling combined approach, providing novel valuable hints for the design of RGD integrin ligands with the desired specificity profile.
- Published
- 2021