Fig. 10: Model of how cell-impermeable kinase inhibitors block viral entry.
From: Cell-impermeable staurosporine analog targets extracellular kinases to inhibit HSV and SARS-CoV-2
a Binding of HSV to cellular receptors (1) triggers intracellular calcium transients (2), which activate phospholipid scramblase-1 (3) leading to the translocation of phospatidylserines and cellular proteins (PDPK1, Akt, PLCγ and possibly others) to the outer leaflet of the plasma membrane (4) where, analogous to the the canonical cytoplasmic signaling pathways, autophosphorylation of PDPK1 triggers phosphorylation of outer leaflet Akt, which, in turn, phosphorylates PLCγ (5). This signaling pathway is required for HSV entry and is associated with subsequent restoration of phospholipid distribution (6). b Cell-impermeable kinase inhibitors (e.g. CIMSS) or antibodies to Akt block the activation of this extracellular signaling pathway (5) and prevent HSV entry resulting in (6) persistence of extracellular PtdS, which may lead to apoptosis.
