The Synthetic Dipeptide Pidotimod Shows a Chemokine-Like Activity through CXC Chemokine Receptor 3 (CXCR3)

Abstract

In recent years immunomodulators have gained a strong interest and represent nowadays an active expanding area of research for the control of microbial diseases and for their therapeutic potential in preventing, treating and reducing the morbidity and mortality of different diseases. Pidotimod (3-L-pyroglutamyl-L-thiaziolidine-4carboxylic acid, PDT) is a synthetic dipeptide, which possesses immunomodulatory properties and exerts a well-defined pharmacological activity against infections, but its real mechanism of action is still undefined. Here, we show that PDT is capable of activating tyrosine phosphorylation-based cell signaling in human primary monocytes and triggering rapid adhesion and chemotaxis. PDT-induced monocyte migration requires the activation of the PI3K/Akt signaling pathway and chemokine receptor CXCR3. Indeed, a mAb to CXCR3 and a specific receptor inhibitor suppressed significantly PDT-dependent chemotaxis, and CXCR3-silenced primary monocytes lost responsiveness to PDT chemoattraction. Moreover, our results highlighted that the PDT-induced migratory activity is sustained by the CXCR3A isoform, since CXCR3-transfected L1.2 cells acquired responsiveness to PDT stimulation. Finally, we show that PDT, as CXCR3 ligands, is also able to direct the migration of IL-2 activated T cells, which express the highest levels of CXCR3 among CXCR3-expressing cells. In conclusion, our study defines a chemokine-like activity for PDT through CXCR3A and points on the possible role that this synthetic dipeptide may play in leukocyte trafficking and function. Since recent studies have highlighted diverse therapeutic roles for molecules which activates CXCR3, our findings call for an exploration of using this dipeptide in different pathological processes.

Proposal for a new therapeutic high dosage of Pidotimod in children with Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome: a randomized controlled study.

“…Moreover, differently to Buongiorno et al [13], we wanted to test the Pidotimod use at higher doses (2 vials of 400mg daily), for a shorter period (up to 3 months). In light of the evidence suggesting that higher Pidotimod concentrations are associated with a more effective immune activity [18], especially against infections, we choce to adopt this therapeutic regimen. Moreover, the latter appeared associated both with a good therapeutic e cacy and a reduced stress of the patients related to long-term treatment.…”

Proposal for a new therapeutic high dosage of Pidotimod in children with periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome: a randomized controlled study

“…Moreover, differently to Buongiorno et al [13], we wanted to test the Pidotimod use at higher doses (2 vials of 400 mg daily), for a shorter period (up to 3 months). In light of the evidence suggesting that higher Pidotimod concentrations are associated with a more effective immune activity [18], especially against infections, we choce to adopt this therapeutic regimen. Moreover, the latter appeared associated both with a good therapeutic efficacy and a reduced stress of the patients related to long-term treatment.…”

Rapamycin as a potent and selective inhibitor of vascular endothelial growth factor receptor in breast carcinoma

“…In contrast to rapamycin, PF-4 affects the CXCR3 ligand. Activated CXCR3 protein will activate the PI3K/Akt pathway downstream [18]. With the combination of both drugs (rapamycin and PF-4), we hypothesized that they would function synergistically against the PI3K/Akt pathway, which would result in a better prognosis.…”