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

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.