Halting the Spread of Herpes Simplex Virus-1: The Discovery of an Effective Dual αvß6/αvß8 Integrin Ligand.
J Med Chem
; 64(10): 6972-6984, 2021 05 27.
Article
em En
| MEDLINE
| ID: mdl-33961417
ABSTRACT
Over recent years, αvß6 and αvß8 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 αvß6-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 αvß8. Among the novel compounds, [RGD-Chg-(NMe)E]-CONH2 (6) turned out to be a potent αvß6/αvß8 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oligopeptídeos
/
Peptídeos Cíclicos
/
Integrinas
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Herpesvirus Humano 1
/
Ligantes
/
Antígenos de Neoplasias
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2021
Tipo de documento:
Article