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.

Halting the Spread of Herpes Simplex Virus-1: The Discovery of an Effective Dual αvβ6/αvβ8 Integrin Ligand / 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.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 64:10(2021), pp. 6972-6984. [10.1021/acs.jmedchem.1c00533]

Halting the Spread of Herpes Simplex Virus-1: The Discovery of an Effective Dual αvβ6/αvβ8 Integrin Ligand

Tomassi S.
Co-primo
Conceptualization
;
D'Amore V. M.
Co-primo
;
Di Leva F. S.
;
Amato J.;Romano B.;Izzo A. A.;Di Maro S.
;
Novellino E.;Marinelli L.
2021

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.
2021
Halting the Spread of Herpes Simplex Virus-1: The Discovery of an Effective Dual αvβ6/αvβ8 Integrin Ligand / 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.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 64:10(2021), pp. 6972-6984. [10.1021/acs.jmedchem.1c00533]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/865397
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